Gene Summary

Gene:HDAC3; histone deacetylase 3
Aliases: HD3, RPD3, KDAC3, RPD3-2
Summary:Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter. It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumor suppressor gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:histone deacetylase 3
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HDAC3 (cancer-related)

Lombard DB, Cierpicki T, Grembecka J
Combined MAPK Pathway and HDAC Inhibition Breaks Melanoma.
Cancer Discov. 2019; 9(4):469-471 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
In this issue, Maertens and colleagues demonstrate that HDAC3 inhibition potentiates the effects of MAPK pathway inhibitors in melanoma, including difficult-to-treat

Zhang M, Pan Y, Tang D, et al.
Low levels of pyruvate induced by a positive feedback loop protects cholangiocarcinoma cells from apoptosis.
Cell Commun Signal. 2019; 17(1):23 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Cancer cells avidly consume glucose and convert it to lactate, resulting in a low pyruvate level. This phenomenon is known as the Warburg effect, and is important for cell proliferation. Although cMyc has often been described as an oncoprotein that preferentially contributes to the Warburg effect and tumor proliferation, mechanisms of action remain unclear. Histone deacetylase 3 (HDAC3) regulates gene expression by removing acetyl groups from lysine residues, as well as has an oncogenic role in apoptosis and contributes to the proliferation of many cancer cells including cholangiocarcinoma (CCA). HDAC inhibitors display antitumor activity in many cancer cell lines. Cancer cells maintain low levels of pyruvate to prevent inhibition of HDAC but the mechanisms remain elusive. The purpose of our study was to explore the role of cMyc in regulating pyruvate metabolism, as well as to investigate whether the inhibitory effect of pyruvate on HDAC3 could hold promise in the treatment of cancer cells.
METHODS: We studied pyruvate levels in CCA cell lines using metabolite analysis, and analyzed the relationship of pyruvate levels and cell proliferation with cell viability analysis. We cultivated CCA cell lines with high or low levels of pyruvate, and then analyzed the protein levels of HDAC3 and apoptotic markers via Western Blotting. We then explored the reasons of low levels of pyruvate by using seahorse analysis and
RESULTS: We confirmed downregulated pyruvate levels in CCA, and defined that high pyruvate levels correlated with reduced cell proliferation levels. Downregulated pyruvate levels decreased the inhibition to HDAC3 and consequently protected CCA cells from apoptosis. Synergistically upregulated LDHA, PKM2 levels resulted in low levels of pyruvate, as well as poor patient survival. We also found that low levels of pyruvate contributed to proliferation of CCA cells and confirmed that the upstream target is cMyc. Conversely, high activity of HDAC3 stabilized cMyc protein by preferential deacetylating cMyc at K323 site, which further contributed to the low pyruvate levels. Finally, this creates a positive feedback loop that maintained the low levels of pyruvate and promoted CCA proliferation.
CONCLUSIONS: Collectively, our findings identify a role for promoting the low pyruvate levels regulated by c-Myc, and its dynamic acetylation in cancer cell proliferation. These targets, as markers for predicting tumor proliferation in patients undergoing clinical treatments, could pave the way towards personalized therapies.

Hu G, He N, Cai C, et al.
HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer.
Pancreatology. 2019; 19(2):383-389 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths worldwide. Despite immune checkpoints based immunotherapy highlights a new therapeutic strategy and achieves a remarkable therapeutic effect in various types of malignant tumors. Pancreatic cancer is one of the non-immunogenic cancers and is resistant to immunotherapy. Programmed death ligand 1 (PD-L1) is expressed on the surface of tumor cells and its level is a key determinant of the checkpoint immunotherapy efficacy. Here, we reported that the specific inhibitor of histone deacetylase 3 (HDAC3) decreased the protein and mRNA level of PD-L1 in pancreatic cancer cells. Furthermore, we showed that HDAC3 was critical for PD-L1 regulation and positively correlated with PD-L1 in PDAC patient specimens. Finally, we demonstrated that HDAC3/signal transducer and activator of transcription 3 (STAT3) pathway transcriptionally regulated PD-L1 expression. Collectively, our data contributes to a better understanding of the function of HDAC3 in cancer immunity and the regulatory mechanism of PD-L1. More importantly, these data suggest that the HDAC3 inhibitors might be used to improve immunotherapy in pancreatic cancer.

Kwon Y, Kim Y, Jung HS, Jeoung D
Role of HDAC3-miRNA-CAGE Network in Anti-Cancer Drug-Resistance.
Int J Mol Sci. 2018; 20(1) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Histone modification is associated with resistance to anti-cancer drugs. Epigenetic modifications of histones can regulate resistance to anti-cancer drugs. It has been reported that histone deacetylase 3 (HDAC3) regulates responses to anti-cancer drugs, angiogenic potential, and tumorigenic potential of cancer cells in association with cancer-associated genes (CAGE), and in particular, a cancer/testis antigen gene. In this paper, we report the roles of microRNAs that regulate the expression of HDAC3 and CAGE involved in resistance to anti-cancer drugs and associated mechanisms. In this review, roles of HDAC3-miRNAs-CAGE molecular networks in resistance to anti-cancer drugs, and the relevance of HDAC3 as a target for developing anti-cancer drugs are discussed.

Deng R, Zhang P, Liu W, et al.
HDAC is indispensable for IFN-γ-induced B7-H1 expression in gastric cancer.
Clin Epigenetics. 2018; 10(1):153 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: B7 homolog 1 (B7-H1) overexpression on tumor cells is an important mechanism of immune evasion in gastric cancer (GC). Elucidation of the regulation of B7-H1 expression is urgently required to guide B7-H1-targeted cancer therapy. Interferon gamma (IFN-γ) is thought to be the main driving force behind B7-H1 expression, and epigenetic factors including histone acetylation are recently linked to the process. Here, we investigated the potential role of histone deacetylase (HDAC) in IFN-γ-induced B7-H1 expression in GC. The effect of Vorinostat (SAHA), a small molecular inhibitor of HDAC, on tumor growth and B7-H1 expression in a mouse GC model was also evaluated.
RESULTS: RNA-seq data from The Cancer Genome Atlas revealed that expression of B7-H1, HDAC1-3, 6-8, and 10 and SIRT1, 3, 5, and 6 was higher, and expression of HDAC5 and SIRT4 was lower in GC compared to that in normal gastric tissues; that HDAC3 and HDAC1 expression level significantly correlated with B7-H1 in GC with a respective r value of 0.42 (p < 0.001) and 0.21 (p < 0.001). HDAC inhibitor (Trichostatin A, SAHA, and sodium butyrate) pretreatment suppressed IFN-γ-induced B7-H1 expression on HGC-27 cells. HDAC1 and HDAC3 gene knockdown had the same effect. SAHA pretreatment or HDAC knockdown resulted in impaired IFN-γ signaling, demonstrated by the reduction of JAK2, p-JAK1, p-JAK2, and p-STAT1 expression and inefficient STAT1 nuclear translocation. Furthermore, SAHA pretreatment compromised IFN-γ-induced upregulation of histone H3 lysine 9 acetylation level in B7-H1 gene promoter. In the grafted mouse GC model, SAHA treatment suppressed tumor growth, inhibited B7-H1 expression, and elevated the percentage of tumor-infiltrating CD8+ T cells.
CONCLUSION: HDAC is indispensable for IFN-γ-induced B7-H1 in GC. The study suggests the possibility of targeting B7-H1 using small molecular HDAC inhibitors for cancer treatment.

Klieser E, Urbas R, Swierczynski S, et al.
HDAC-Linked "Proliferative" miRNA Expression Pattern in Pancreatic Neuroendocrine Tumors.
Int J Mol Sci. 2018; 19(9) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Epigenetic factors are essentially involved in carcinogenesis, tumor promotion, and chemoresistance. Two epigenetic key players are miRNAs and histone deacetylases (HDACs). As previously shown by own theoretical databank analysis, the crosstalk between miRNAs and HDACs is relevant in different human chronic diseases and cancerogenic pathways. We aimed to investigate a potential connection between the expression of a well-defined subset of "proliferation-associated" miRNAs and the expression of HDACs as well as clinical parameters in pancreatic neuroendocrine tumors (pNETs).
MATERIALS AND METHODS: Expression levels of miRNA132-3p, miRNA145-5p, miRNA183-5p, miRNA34a-5p, and miRNA449a in 57 pNETs resected between 1997 and 2015 were measured and linked to the immunohistochemical expression pattern of members of the four HDAC classes on human tissue microarrays. All pNET cases were clinically and pathologically characterized according to published guidelines. Correlation analysis revealed a significant association between expression of specific miRNAs and two members of the HDAC family (HDAC3 and HDAC4). Additionally, a linkage between miRNA expression and clinico-pathological parameters like grading, TNM-staging, and hormone activity was found. Moreover, overall and disease-free survival is statistically correlated with the expression of the investigated miRNAs. Overall, we demonstrated that specific miRNAs could be linked to HDAC expression in pNETs. Especially miRNA449a (associated with HDAC3/4) seems to play an important role in pNET proliferation and could be a potential prognostic factor for poor survival. These first data could help, to improve our knowledge of the complex interactions of the epigenetic drivers in pNETs for further therapeutic approaches.

Zhong S, Fan Y, Wu B, et al.
HDAC3 Expression Correlates with the Prognosis and Grade of Patients with Glioma: A Diversification Analysis Based on Transcriptome and Clinical Evidence.
World Neurosurg. 2018; 119:e145-e158 [PubMed] Related Publications
OBJECTIVE: This study aimed to clarify the relationship between histone deacetylase 3 (HDAC3) expression and the prognosis as well as the grade of patients with glioma.
METHODS: The quantitative real-time polymerase chain reaction was profiled to examine the HDAC3 expression in glioma and normal glial cell lines. An Oncomine database analysis and prognosis analysis were performed. The correlation between World Health Organization (WHO) grade and HDAC3 was analyzed by Spearman rank correlation test. A meta-analysis was performed to confirm the conclusion.
RESULTS: HDAC3 RNA overexpression in glioma cell lines was detected (P < 0.05). Four data sets were screened from the Oncomine database and showed that the expression level of HDAC3 was consistently higher in glioma than in normal tissue (P < 0.001). The prognostic analysis of 325 glioma samples from the Chinese Glioma Genome Atlas showed that patients with low HDAC3 expression had significantly better overall survival (OS) and progression-free survival (PFS) than did patients with high HDAC3 expression [hazard ratio [HR], 1.992; 95% confidence interval [CI], 1.490-2.662; P < 0.0001 and HR, 1.874; 95% CI, 1.412-2.487; P < 0.0001, respectively]. Both the WHO grade III group and the WHO grade IV group expressed significantly higher messenger RNA (mRNA) level than did the WHO grade II group (P < 0.05). Four cohort studies consisting of 490 patients were included in the meta-analysis. The pooled data of subgroup analysis showed significantly longer OS in low HDAC3 mRNA level [HR, 3.38; 95% CI, 1.80-6.37; P = 0.0002].
CONCLUSIONS: HDAC3 mRNA was expressed more in glioma than in the normal glial cell line. Low HDAC3 mRNA expression levels predicted better OS. HDAC3 expression could be a biomarker to discriminate glioma grade.

Okonkwo A, Mitra J, Johnson GS, et al.
Heterocyclic Analogs of Sulforaphane Trigger DNA Damage and Impede DNA Repair in Colon Cancer Cells: Interplay of HATs and HDACs.
Mol Nutr Food Res. 2018; 62(18):e1800228 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
SCOPE: DNA repair inhibitors have broad clinical applications in tumor types with DNA repair defects, including colorectal cancer (CRC). Structural analogs of the anticancer agent sulforaphane (SFN) were investigated as modifiers of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity, and for effects on DNA damage/repair pertinent to human CRC.
METHODS AND RESULTS: In the polyposis in rat colon (Pirc) model, single oral administration of SFN and structurally related long-chain isothiocyanates (ITCs) decreased histone deacetylase 3 (HDAC3) expression and increased pH2AX levels markedly in adenomatous colon polyps, extending prior observations on HDAC3 inhibition/turnover in cell-based assays. Colon cancer cells at a high initial plating density had diminished cytotoxicity from SFN, whereas novel tetrazole-containing heterocyclic analogs of SFN retained their efficacy. The potent SFN analogs triggered DNA damage, cell cycle arrest, apoptosis, and loss of a key DNA repair regulator, C-terminal binding protein (CtBP) interacting protein (CtIP). These SFN analogs also altered HAT/HDAC activities and histone acetylation status, lowered the expression of HDAC3, P300/CBP-associated factor (PCAF) and lysine acetyltransferase 2A (KAT2A/GCN5), and attenuated homologous recombination (HR)/non-homologous end joining (NHEJ) repair activities in colon cancer cells.
CONCLUSION: Novel tetrazole-containing heterocyclic analogs of SFN provide a new avenue for chemosensitization in colon cancer cells via modulation of HAT/HDAC activities and associated DNA damage/repair signaling pathways.

Gao HY, Wang W, Luo XG, et al.
Screening of prognostic risk microRNAs for acute myeloid leukemia.
Hematology. 2018; 23(10):747-755 [PubMed] Related Publications
Objectives This study aimed to investigate the risk miRNAs (microRNAs) for AML (acute myeloid leukemia) prognosis and related regulatory mechanisms. Methods MiRNA and gene expression data, as well as clinical data of 176 patients were first downloaded from TCGA. Then miRNAs and genes significantly affecting the survival time based on KM survival curve were identified using Log Rank test. Next, COX proportional-hazard regression analysis was performed to screen the risk miRNAs (P-value < 0.05). Common genes from survival analysis and predicted by miRWalk were used to construct the miRNA regulatory network with the risk miRNAs. Finally, a protein-protein interaction (PPI) network was constructed, as well as functional annotation and pathway enrichment analysis. Results The survival analysis revealed 33 miRNAs and 1,377 genes significantly affecting the survival time. HR values of nine miRNAs (up-regulated hsa-mir-606, 520a, 137, 362, 599, 600, 202, 639and down-regulated 502) were either >1 or <1. The miRNA regulatory network contained 477 nodes and 944 edges. The top ten genes of the constructed PPI network were EGFR, EIF4G1, REL, TOP1, COL14A1, HDAC3, MRPL49, PSMA2, TOP2A and VCAM1 successively. According to pathway enrichment analysis, 6 KEGG pathways and 6 REACTOME pathways were obtained respectively. Conclusion Up-regulated hsa-mir-520a, 599, 606, 137 and 362 may increase the prognostic risk for AML patients via regulating the expression of corresponding target genes, especially COL14A1, HDAC3, REL, EGFR, PSMA2, EIF4G1, MRPL49 and TOP1.

Cui Z, Xie M, Wu Z, Shi Y
Relationship Between Histone Deacetylase 3 (HDAC3) and Breast Cancer.
Med Sci Monit. 2018; 24:2456-2464 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND The modification of histone acetylation and deacetylation is the most important mechanism of chromatin remodeling. These modifications are a subset of epigenetic alterations which affect tumorigenesis and progression through changes in gene expression and cell growth. Results of histone modification studies prompted us to explore the therapeutic and prognostic significance of histone deacetylase 3 (HDAC3) expression in patients with breast cancer. MATERIAL AND METHODS Immunohistochemical (IHC) staining was used to detect HDAC3 expression in a tissue microarray (TMA) that included 145 patients diagnosed with invasive ductal breast carcinoma. IHC scoring was used to evaluate the staining intensity and the proportion of positive cells. RESULTS HDAC3 expression was significantly correlated with estrogen receptor (ER)-negative expression (P=0.036) and progesterone receptor (PR)-negative expression (P=0.024). Additionally, HDAC3 expression was significantly positively correlated with human epidermal growth factor 2 (HER2) overexpression (P=0.037). Our study also indicated that high expression of HDAC3 was more frequently observed in breast tumors with PT2 classification (74%) versus PT1 (50.0%) and PT3 (71.4%) (P=0.040). Furthermore, HDAC3 was correlated with clinical stage II (P=0.046). Univariate and multivariate survival analyses showed that high expression of HDAC3 was correlated with poor overall survival (OS) (P=0.029 and P=0.033, respectively) in patients without lymph node involvement. CONCLUSIONS High HDAC3 expression is closely correlated with ER-negative expression, PR-negative expression, HER2 overexpression, PT stage, and clinical stage of breast tumors. HDAC3 may be an appropriate prognostic indicator in patients with invasive ductal breast cancer.

Jia L, Wu D, Wang Y, et al.
Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.
Oncogene. 2018; 37(25):3340-3355 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

Cheng B, Tang S, Zhe N, et al.
Low expression of GFI-1 Gene is associated with Panobinostat-resistance in acute myeloid leukemia through influencing the level of HO-1.
Biomed Pharmacother. 2018; 100:509-520 [PubMed] Related Publications
To improve the treatment outcomes of acute myeloid leukemia (AML), epigenetic modification has been widely tested and used in recent years. However, drug-resistance is still a choke point to cure the malignancy. The growth factor independent 1 transcriptional repressor (GFI-1), as a zinc-finger transcriptional repressor, can bind histone deacetylases to allow the transcriptional repression. According to the finding of our study, AML patients with low level of GFI-1 not only implicated poor prognosis but also caused Panobinostat-resistance. In our prevent study revealed that heme oxygenase-1(HO-1) was one of the main factors leading to chemotherapy sensitivity to AML. Thus, this study tried to test the correlation between GFI-1 and HO-1. Our study discovered that AML patients with lower expression of GFI-1 had higher level of HO-1, HDAC1, HDAC2 and HDAC3, which resulted in poor prognosis in AML. The results of the in vitro study were the same. Panobinostat is a promising new class of anti-cancer drugs in AML. However, knocking down GFI-1 by siRNA could eliminate the Panobinostat-induced cell apoptosis. Subsequently, we utilized ZnPP to down regulate the level of HO-1, finding that the Panobinostat-resistance between the low level of GFI-1 and empty vector had eased. After further exploring the mechanism, it could be found that with knock down GFI-1, the phosphorylation of Akt and PI3K could be activated. Subsequently, Akt pathway and HO-1 inhibitor were utilized respectively and the resistance was reversed. It suggested that the resistance of Panobinostat to AML cells at low level of GFI-1 was mainly due to up-regulated level of HO-1 through the PI3K-Akt pathway.

Tang D, Xu L, Zhang M, et al.
Metformin facilitates BG45‑induced apoptosis via an anti‑Warburg effect in cholangiocarcinoma cells.
Oncol Rep. 2018; 39(4):1957-1965 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is a highly lethal malignancy with an often late diagnosis and consequent poor prognosis. Chemotherapy is the only therapeutic strategy for most patients. Compared to normal cells, tumor cells preferentially metabolize glucose to lactate, even in aerobic conditions. Such metabolic alterations not only support the growth and invasion of tumor cells, but also promote their chemoresistance. The purpose of our study was to explore the role of metformin in regulating the metabolism of CCA, as well as to investigate whether metformin could act as a chemosensitizer of the HDAC3 inhibitor BG45, and therefore have potential for the treatment of CCA. Through bioinformatic analysis, we found that aberrant metabolism contributed to the proliferation of CCA cells. Seahorse XF96 Extracellular Flux Analyzer analysis and lactate production analysis showed that metformin could act as a suppressor of the Warburg effect in CCA cells. Western blotting showed that metformin decreased the expression of LDHA, which plays a key role in the Warburg effect. However, suppression of the Warburg effect was not sufficient to induce CCA cellular apoptosis. According to our previous research, which showed that an HDAC3 inhibitor (MI192) was involved in CCA apoptosis, we observed that metformin combined with BG45 (a novel specific HDAC3 inhibitor) effectively induced the apoptosis of CCA cells in vitro. Furthermore, in vivo experiments revealed that the combined treatment with metformin and BG45 markedly reduced CCA growth in a CCA xenograft model. Our data revealed that reversing the Warburg effect with metformin sensitizes cells to the antitumor effects of HDAC3 inhibitors. This provides a rationale for using the combination of metformin and BG45 as a new therapeutic strategy in the treatment of CCA.

He P, Li K, Li SB, et al.
Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancer.
Int J Oncol. 2018; 52(4):1305-1316 [PubMed] Related Publications
A-kinase anchor protein 12 (AKAP12; also known as Gravin) functions as a tumor suppressor in several human primary cancers. However, the potential correlation between histone deacetylase 3 (HDAC3) and AKAP12 and the underlying mechanisms remain unclear. Thus, in this study, in an aim to shed light into this matter, the expression levels of HDAC3 and AKAP12 in 96 colorectal cancer (CRC) and adjacent non-cancerous tissues, as well as in SW480 cells were examined by immunohistochemical, RT-qPCR and western blot analyses. The effects of HDAC3 and AKAP12 on the proliferation, apoptosis and metastasis of CRC cells were examined by cell counting kit-8 (CCK-8) assay, colony formation assays, flow cytometry, cell cycle analysis and Transwell assays. The results revealed that the reduction or loss of AKAP12 expression was detected in 69 (71.8%) of the 96 tissue specimens, whereas HDAC3 was upregulated in 50 (52.1%) of the 96 tumor tissue specimens. AKAP12 expression was markedly increased upon treatment with the HDAC3 inhibitors, trichostatin A (TSA) and RGFP966, at both the mRNA and protein level. Mechanistically, the direct binding of HDAC3 within the intron-1 region of AKAP12 was identified to be indispensable for the inhibition of AKAP12 expression. Moreover, the proliferation, colony-forming ability, cell cycle progression and the migration of the CRC cells were found to be promoted in response to AKAP12 silencing or AKAP12/HDAC3 co-silencing, whereas transfection with si-HDAC3 yielded opposite effects. Apart from the elevated expression of the anti-apoptotic protein, Bcl-2, after AKAP12 knockdown, the increased activity of PI3K/AKT signaling was found to be indispensable for AKAP12-mediated colony formation and migration. On the whole, these findings indicate that AKAP12 may be a potential prognostic predictor and therapeutic target for the treatment of CRC in combination with HDAC3.

Huang R, Zhang X, Sophia S, et al.
Clinicopathological features and prediction values of HDAC1, HDAC2, HDAC3, and HDAC11 in classical Hodgkin lymphoma.
Anticancer Drugs. 2018; 29(4):364-370 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Histone deacetylases (HDACs) are involved in multiple physical and pathological processes in classical Hodgkin lymphoma (cHL). The prognostic value of HDACs in cHL patients has not been discussed. The aim of the current study is to investigate the HDAC1, HDAC2, HDAC3, and HDAC11 expressions, and to evaluate the correlation of HDAC1, HDAC2, HDAC3, and HDAC11 expressions with the survival rate in cHL patients. We retrospectively analyzed clinicopathological data of 28 patients who were diagnosed with cHL between August 2002 and March 2010. Immunohistochemistry was used to detect the expression of HDAC1, HDAC2, HDAC3, and HDAC11 in these patients. The results showed that HDAC1, HDAC3, and HDAC11 were expressed at a higher level in Hodgkin Reed-Sternberg cells, whereas HDAC2 was expressed at a lower level in Hodgkin Reed-Sternberg cells. The expression of HDAC2 had a relationship with pathological type (P=0.012). There was also a correlation between the expression of HDAC11 and the erythrocyte sedimentation rate (P=0.054). Other clinicopathological parameters had no significant correlation with the expression of HDAC1, HDAC2, HDAC3, and HDAC11 in terms of survival (P>0.05). The 10-year total survival rate by Cox multivariate analysis, after taking into account all clinical and pathologic factors, showed that bulky disease retained significance (P=0.028). Higher expression of HDAC1 predicted shorter progression-free survival and overall survival (OS) in cHL patients (P<0.05, in both cases), and higher expression of HDAC11 might be correlated with lower OS (P=0.05). The study showed that the expressions of HDAC2 and HDAC11 have a particular relationship with the pathologic subtype. Increased expression of HDAC1 was correlated negatively with progression-free survival and OS, and increased expression of HDAC11 had a borderline relationship with the OS rate in patients with cHL.

Peng Z, Zhou W, Zhang C, et al.
Curcumol Controls Choriocarcinoma Stem-Like Cells Self-Renewal via Repression of DNA Methyltransferase (DNMT)- and Histone Deacetylase (HDAC)-Mediated Epigenetic Regulation.
Med Sci Monit. 2018; 24:461-472 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND Cancer stem cells (CSCs), in choriocarcinoma and other carcinomas, possess the ability of self-renewal and multilineage differentiation potential. We previous isolated choriocarcinoma cancer stem-like cells (CSLCs), which hold the stemness characteristics of CSCs. Epigenetic modifications have emerged as drivers in tumorigenesis, but the mechanisms of CSCs are largely unknown, and new drug therapies are needed to break the persistence of CSCs. MATERIAL AND METHODS Quantitative real-time PCR (qRT-PCR) and Western blot analysis were performed to detect the expression of DNMTs, HDACs, and stemness-genes. DNMTs and HDACs silencing and overexpressing lentivirus were transfected into JEG-3 cells to investigate the epigenetic functions in CSLCs. In vivo expression of curcumol effects of CSLCs on DNMTs and HDACs were analyzed by immunohistochemistry. RESULTS Expression of DNMT1, DNMT3b, HDAC1, and HDAC3 were increased in choriocarcinoma CSLCs. Consistent with the inhibitory effect of 5-AzaC and TSA on CSLCs, DNMT/HDAC knockdown displayed significant repression of self-renewal in CSLCs. Curcumol inhibited the stemness ability of CSLCs in vitro and in vivo, and the inhibitory effect we observed was mediated in part through repressing activity of DNMTs and HDACs. Importantly, curcumol showed a better effect than DNMT and HDAC inhibitors combined in eliminating CSLCs. CONCLUSIONS These findings indicate that DNMT- and HDAC-mediated epigenetic regulation plays an important role in the biology of choriocarcinoma CSLCs, and curcumol has the potential to be a new drug to fight CSLCs, warranting further investigation of epigenetic-based therapies.

Yang M, Dang X, Tan Y, et al.
I-7ab inhibited the growth of TNBC cells via targeting HDAC3 and promoting the acetylation of p53.
Biomed Pharmacother. 2018; 99:220-226 [PubMed] Related Publications
Triple negative breast cancer (TNBC) is a heterogenous disease with high aggressive and poor outcome. The lack of biomarkers and targeted therapies makes it a challenge for the treatment of TNBC. Histone deacetylase inhibitors (HDACis) are emerging as novel anti-tumor agents in many types of human cancers. In this study, we found that I-7ab, a novel HDACi, inhibited the cell viability of TNBC cells and induced the cell apoptosis. Mechanistically, I-7ab specifically decreased the expression of HDAC3 and promoted the acetylation of p53 at both Lys373 and Lys382 amino acids. The up-regulated acetylation of p53 promoted the transcriptional activity of p53 and induced the expression of p21, which consequently caused cell cycle arrest at G1 phase. Administration of I-7ab inhibited the colony formation of TNBC cells. Collectively, these results indicated I-7ab as a promising anti-cancer agent in the treatment of TNBC.

McLeod AB, Stice JP, Wardell SE, et al.
Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancer.
Prostate. 2018; 78(4):266-277 [PubMed] Related Publications
BACKGROUND: Whereas the androgen receptor (AR) signaling axis remains a therapeutic target in castration-resistant prostate cancer (CRPC), the emergence of AR mutations and splice variants as mechanisms underlying resistance to contemporary inhibitors of this pathway highlights the need for new therapeutic approaches to target this disease. Of significance in this regard is the considerable preclinical data, indicating that histone deacetylase (HDAC) inhibitors may have utility in the treatment of CRPC. However, the results of clinical studies using HDAC inhibitors (directed against HDAC1, 2, 3, and 8) in CRPC are equivocal, a result that some have attributed to their ability to induce an epithelial to mesenchymal transition (EMT) and neuroendocrine differentiation. We posited that it might be possible to uncouple the beneficial effects of HDAC inhibitors on AR signaling from their undesired activities by targeting specific HDACs as opposed to using the pan-inhibitor strategy that has been employed to date.
METHODS: The relative abilities of pan- and selective-Class I HDAC inhibitors to attenuate AR-mediated target gene expression and proliferation were assessed in several prostate cancer cell lines. Small interfering RNA (siRNA)-mediated knockdown approaches were used to confirm the importance of of HDAC 1, 2, and 3 expression in these processes. Further, the ability of each HDAC inhibitor to induce the expression of EMT markers (RNA and protein) and EMT-like phenotype(s) (migration) were also assessed. The anti-tumor efficacy of a HDAC3-selective inhibitor, RGFP966, was compared to the pan-HDAC inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in the 22Rv1 xenograft model.
RESULTS: Using genetic and pharmacological approaches we demonstrated that a useful inhibition of AR transcriptional activity, absent the induction of EMT, could be achieved by specifically inhibiting HDAC3. Significantly, we also determined that HDAC3 inhibitors blocked the activity of the constitutively active AR V7-splice variant and inhibited the growth of xenograft tumors expressing this protein.
CONCLUSIONS: Our studies provide strong rationale for the near-term development of specific HDAC3 inhibitors for the treatment of CRPC.

Xu G, Zhu H, Zhang M, Xu J
Histone deacetylase 3 is associated with gastric cancer cell growth via the miR-454-mediated targeting of CHD5.
Int J Mol Med. 2018; 41(1):155-163 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Gastric cancer (GC) is the third leading cause of cancer-related mortality in China and worlwide; hence, the identification of GC-related genes is necessary for the development of effective treatment strategies. In this study, histone deacetylase 3 (HDAC3) was identified as the most significantly upregulated cancer-related gene in GC tissues by microarray. In accordance with this, HDAC3 expression was found to be upregulated in GC cell lines/tissues. Further experiments indicated that the knockdown of HDAC3 decreased GC cell viability, reduced the colony formation number and decreased tumor weight. To explore the underlying mechanisms, the overexpression of HDAC3 was induced by transfection with an overexpression plasmid, followed by miRNA microarray, and we identified miR-454 as the most markedly upregulated miRNA. Accordingly, miR-454 expression was upregulated in GC cell lines/tissues and a high level of miR-454 indicated a high HDAC3 expression in GC tissues, and miR-454 knockdown reduced cell viability. In addition, a high level of miR-454 was significantly associated with an advanced clinical stage, lymph node metastases and a poor prognosis of patients with GC. Furthermore, CHD5 was identified as a direct target of miR-454. CHD5 was downregulated in GC tissues/cell lines and the expresssion of CHD5 inversely correlated with the level of miR-454 in GC tissues. Taken together, these observations indicate that HDAC3 is associated with GC cell growth via the miR-454-mediated targeting of CHD5.

Mao Z, Li H, Du B, et al.
LncRNA DANCR promotes migration and invasion through suppression of lncRNA-LET in gastric cancer cells.
Biosci Rep. 2017; 37(6) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Gastric cancer (GC) is one of the most prevalent gastrointestinal malignancies. Long noncoding RNA (lncRNA) DANCR is a newly identified oncogenic lncRNA. However, the functional role and underlying molecular mechanisms of DANCR involved in GC progress remain unclear. In the present study, we investigated the biological function and underlying mechanisms of DANCR in GC cell migration and invasion. The results showed that knockdown of DANCR inhibited migration and invasion of GC cells, whereas overexpression of DANCR showed the opposite effect. Further investigation demonstrated that lncRNA-LET was a

Guo X, Zhu Y, Hong X, et al.
miR-181d and c-myc-mediated inhibition of CRY2 and FBXL3 reprograms metabolism in colorectal cancer.
Cell Death Dis. 2017; 8(7):e2958 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Colorectal cancer (CRC) is the second major cause of tumor-related deaths. MicroRNAs (miRNAs) have pivotal roles in CRC progression. Here, we describe the effect of miR-181d on CRC cell metabolism and underlying molecular mechanism. Our data firmly demonstrated that knockdown of miR-181d suppressed CRC cell proliferation, migration, and invasion by impairing glycolysis. Mechanistically, miR-181d stabilized c-myc through directly targeting the 3'-UTRs of CRY2 and FBXL3, which subsequently increased the glucose consumption and the lactate production. Inhibition of c-myc via siRNA or small molecular inhibitor abolished the oncogenic effects of miR-181d on the growth and metastasis of CRC cells. Furthermore, c-myc/HDAC3 transcriptional suppressor complex was found to co-localize on the CRY2 and FBXL3 promoters, epigenetically inhibit their transcription, and finally induce their downregulation in CRC cells. In addition, miR-181d expression could be directly induced by an activation of c-myc signaling. Together, our data indicate an oncogenic role of miR-181d in CRC by promoting glycolysis, and miR-181d/CRY2/FBXL3/c-myc feedback loop might be a therapeutic target for patients with CRC.

Yin Y, Zhang M, Dorfman RG, et al.
Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition.
Cell Death Dis. 2017; 8(6):e2856 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Histone deacetylase 3 (HDAC3) has an oncogenic role in apoptosis and contributes to the proliferation of cancer cells. MI192 is a novel HDAC3-specific inhibitor that displays antitumor activity in many cancer cell lines. However, the role of HDAC3 and the antitumor activity of its inhibitor MI192 are not known in cholangiocarcinoma (CCA). The present study aims to identify the target of MI192 in CCA as well as evaluate its therapeutic efficacy. CCK8 and colony formation assays showed that HDAC3 overexpression promotes proliferation in CCA cell lines. HDAC3 knockdown or treatment with MI192 decreased CCA cell growth and increased caspase-dependent apoptosis, while apoptosis was partially rescued by HDAC3 overexpression. We demonstrated that MI192 can inhibit the deacetylation activity of HDAC3 and its downstream targets in vitro, and MI192 inhibited xenograft tumor growth in vivo. Immunochemistry showed that HDAC3 was upregulated in CCA tissues compared with adjacent normal tissues, and this was correlated with reduced patient survival. Taken together, these results demonstrate for the first time that MI192 targets HDAC3 and induces apoptosis in human CCA cells. MI192 therefore shows the potential as a new drug candidate for CCA therapy.

Harada T, Ohguchi H, Grondin Y, et al.
HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications.
Leukemia. 2017; 31(12):2670-2677 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clinical efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clinical activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1 or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1 expression is regulated by c-Myc, and HDAC3 inhibition triggers degradation of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), respectively, triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.

Yang F, Ma Q, Liu Z, et al.
Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ERα-Regulated Transcriptional Program.
Mol Cell. 2017; 66(3):321-331.e6 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GRs) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here we report that, in breast cancer cells, liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and it leads to the inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen E

Long J, Fang WY, Chang L, et al.
Targeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage response.
Leukemia. 2017; 31(12):2761-2770 [PubMed] Related Publications
Resistance to cytotoxic chemotherapy drugs remains as the major cause of treatment failure in acute myeloid leukemia. Histone deacetylases (HDAC) are important regulators to maintain chromatin structure and control DNA damage; nevertheless, how each HDAC regulates genome stability remains unclear, especially under genome stress conditions. Here, we identified a mechanism by which HDAC3 regulates DNA damage repair and mediates resistance to chemotherapy drugs. In addition to inducing DNA damage, chemotherapy drugs trigger upregulation of HDAC3 expression in leukemia cells. Using genetic and pharmacological approaches, we show that HDAC3 contributes to chemotherapy resistance by regulating the activation of AKT, a well-documented factor in drug resistance development. HDAC3 binds to AKT and deacetylates it at the site Lys20, thereby promoting the phosphorylation of AKT. Chemotherapy drug exposure enhances the interaction between HDAC3 and AKT, resulting in decrease in AKT acetylation and increase in AKT phosphorylation. Whereas HDAC3 depletion or inhibition abrogates these responses and meanwhile sensitizes leukemia cells to chemotoxicity-induced apoptosis. Importantly, in vivo HDAC3 suppression reduces leukemia progression and sensitizes MLL-AF9

Zhang L, Cai M, Gong Z, et al.
Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis.
J Clin Invest. 2017; 127(6):2159-2175 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Geminin expression is essential for embryonic development and the maintenance of chromosomal integrity. In spite of this protective role, geminin is also frequently overexpressed in human cancers and the molecular mechanisms underlying its role in tumor progression remain unclear. The histone deacetylase HDAC3 modulates transcription factors to activate or suppress transcription. Little is known about how HDAC3 specifies substrates for modulation among highly homologous transcription factor family members. Here, we have demonstrated that geminin selectively couples the transcription factor forkhead box O3 (FoxO3) to HDAC3, thereby specifically facilitating FoxO3 deacetylation. We determined that geminin-associated HDAC3 deacetylates FoxO3 to block its transcriptional activity, leading to downregulation of the downstream FoxO3 target Dicer, an RNase that suppresses metastasis. Breast cancer cells depleted of geminin or HDAC3 exhibited poor metastatic potential that was attributed to reduced suppression of the FoxO3-Dicer axis. Moreover, elevated levels of geminin, HDAC3, or both together with decreased FoxO3 acetylation and reduced Dicer expression were detected in aggressive human breast cancer specimens. These results underscore a prominent role for geminin in promoting breast cancer metastasis via the enzyme-substrate-coupling mechanism in HDAC3-FoxO3 complex formation.

Singh VP, Katta S, Kumar S
WD-repeat protein WDR13 is a novel transcriptional regulator of c-Jun and modulates intestinal homeostasis in mice.
BMC Cancer. 2017; 17(1):148 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: WDR13 is a member of the WD repeat protein family and is expressed in several tissues of human and mice. Previous studies in our laboratory showed that the lack of this gene in mice resulted in mild obesity, hyperinsulinemia, enhanced beta cell proliferation and protection from inflammation. However, the molecular mechanism of WDR13 action is not well understood.
METHODS: In the present study, we used AOM/DSS to induce colitis-mediated colorectal tumor after establishing expression of Wdr13 gene in colon. Further, we have used human colon cancer cell lines, HT29 and COLO205, and mouse primary embryonic fibroblast to understand the molecular mechanism of WDR13 action.
RESULTS: We observed that mice lacking Wdr13 gene have reduced number of tumors and are more susceptible to DSS-induced colon ulcers. We also show that WDR13 is a part of multi protein complex c-Jun/NCoR1/HDAC3 and it acts as a transcriptional activator of AP1 target genes in the presence of JNK signal. Consistent with in vitro data, we observed reduced expression of AP1 target genes in colon after AOM/DSS treatment in Wdr13 knockout mice as compared to that in wild type.
CONCLUSION: Mice lacking Wdr13 gene showed reduced expression of AP1 target genes and protection from colitis-induced colorectal tumors.

Cacan E
Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells.
Cell Biol Int. 2017; 41(3):328-339 [PubMed] Related Publications
The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4-1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4-1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells.

Höpken UE
Targeting HDAC3 in CREBBP-Mutant Lymphomas Counterstrikes Unopposed Enhancer Deacetylation of B-cell Signaling and Immune Response Genes.
Cancer Discov. 2017; 7(1):14-16 [PubMed] Related Publications
The cellular phenotype of B-cell lymphomas arising from B cells undergoing germinal center reactions, such as follicular lymphoma and diffuse large B-cell lymphoma, is strongly shaped by mutations in chromatin-modifying genes. The work presented by Jiang and colleagues addresses how somatic mutations in CREBBP disable acetylation and cause unopposed deacetylation by BCL6/SMRT/HDAC3 complexes on enhancers of B-cell signaling and immune response genes. This opens a therapeutic avenue toward targeted inhibition of CREBBP-mutant lymphomas by HDAC inhibitors. Cancer Discov; 7(1); 14-6. ©2017 AACRSee related article by Jiang et al., p. 38.

Phelps MP, Bailey JN, Vleeshouwer-Neumann T, Chen EY
CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma.
Proc Natl Acad Sci U S A. 2016; 113(52):15090-15095 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR-associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan-HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity.

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