LATS2

Gene Summary

Gene:LATS2; large tumor suppressor kinase 2
Aliases: KPM
Location:13q12.11
Summary:This gene encodes a serine/threonine protein kinase belonging to the LATS tumor suppressor family. The protein localizes to centrosomes during interphase, and early and late metaphase. It interacts with the centrosomal proteins aurora-A and ajuba and is required for accumulation of gamma-tubulin and spindle formation at the onset of mitosis. It also interacts with a negative regulator of p53 and may function in a positive feedback loop with p53 that responds to cytoskeleton damage. Additionally, it can function as a co-repressor of androgen-responsive gene expression. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:serine/threonine-protein kinase LATS2
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
Show (20)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Messenger RNA
  • Mutation
  • Neoplastic Cell Transformation
  • Wings, Animal
  • Cancer Gene Expression Regulation
  • Neoplasm Invasiveness
  • Gene Expression Profiling
  • Signal Transducing Adaptor Proteins
  • Vimentin
  • MicroRNAs
  • LATS2
  • Osteosarcoma
  • Zyxin
  • Cell Proliferation
  • Xenograft Models
  • Biomarkers, Tumor
  • Transcription
  • Non-Small Cell Lung Cancer
  • Wnt Signaling Pathway
  • Promoter Regions
  • Tumor Suppressor Gene
  • Zinc Finger E-box-Binding Homeobox 1
  • Ubiquitination
  • HEK293 Cells
  • RTPCR
  • Staging
  • Ubiquitin-Protein Ligases
  • ras Proteins
  • Phosphorylation
  • DNA Methylation
  • Lung Cancer
  • Nuclear Proteins
  • Cell Movement
  • Mesothelioma
  • Down-Regulation
  • Protein-Serine-Threonine Kinases
  • Transcription Factors
  • Phosphoproteins
  • Chromosome 13
  • Apoptosis
  • Tumor Suppressor Proteins
  • siRNA
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: LATS2 (cancer-related)

Ito T, Nakamura A, Tanaka I, et al.
CADM1 associates with Hippo pathway core kinases; membranous co-expression of CADM1 and LATS2 in lung tumors predicts good prognosis.
Cancer Sci. 2019; 110(7):2284-2295 [PubMed] Free Access to Full Article Related Publications
Cell adhesion molecule-1 (CADM1) is a member of the immunoglobulin superfamily that functions as a tumor suppressor of lung tumors. We herein demonstrated that CADM1 interacts with Hippo pathway core kinases and enhances the phosphorylation of YAP1, and also that the membranous co-expression of CADM1 and LATS2 predicts a favorable prognosis in lung adenocarcinoma. CADM1 significantly repressed the saturation density elevated by YAP1 overexpression in NIH3T3 cells. CADM1 significantly promoted YAP1 phosphorylation on Ser 127 and downregulated YAP1 target gene expression at confluency in lung adenocarcinoma cell lines. Moreover, CADM1 was co-precipitated with multiple Hippo pathway components, including the core kinases MST1/2 and LATS1/2, suggesting the involvement of CADM1 in the regulation of the Hippo pathway through cell-cell contact. An immunohistochemical analysis of primary lung adenocarcinomas (n = 145) revealed that the histologically low-grade subtype frequently showed the membranous co-expression of CADM1 (20/22, 91% of low-grade; 61/91, 67% of intermediate grade; and 13/32, 41% of high-grade subtypes; P < 0.0001) and LATS2 (22/22, 100% of low-grade; 44/91, 48% of intermediate-grade; and 1/32, 3% of high-grade subtypes; P < 0.0001). A subset analysis of disease-free survival revealed that the membranous co-expression of CADM1 and LATS2 was a favorable prognosis factor (5-year disease-free survival rate: 83.8%), even with nuclear YAP1-positive expression (5-year disease-free survival rate: 83.7%), whereas nuclear YAP1-positive cases with the negative expression of CADM1 and LATS2 had a poorer prognosis (5-year disease-free survival rate: 33.3%). These results indicate that the relationship between CADM1 and Hippo pathway core kinases at the cell membrane is important for suppressing the oncogenic role of YAP1.

Guo C, Liang C, Yang J, et al.
LATS2 inhibits cell proliferation and metastasis through the Hippo signaling pathway in glioma.
Oncol Rep. 2019; 41(5):2753-2761 [PubMed] Free Access to Full Article Related Publications
As a core kinase in the Hippo pathway, large tumor suppressor kinase 2 (LATS2) regulates cell proliferation, migration and invasion through numerous signaling pathways. However, its functions on cell proliferation, migration and invasion in glioma have yet to be elucidated. The present study revealed that LATS2 was downregulated in glioma tissues and cells, as determined by reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry. In addition, Cell Counting Kit‑8, scratch wound healing and Transwell assays revealed that overexpression of LATS2 in U‑372 MG cells inhibited cell proliferation, migration and invasion. Furthermore, western blot analysis indicated that the expression levels of phosphorylated (p)‑yes‑associated protein and p‑tafazzin were increased in cells with LATS2 overexpression. These results indicated that LATS2 is a potential tumor suppressor, and downregulation of LATS2 in glioma may contribute to cancer progression.

Kim E, Ahn B, Oh H, et al.
High Yes-associated protein 1 with concomitant negative LATS1/2 expression is associated with poor prognosis of advanced gastric cancer.
Pathology. 2019; 51(3):261-267 [PubMed] Related Publications
The Hippo pathway is a tumour-suppressive pathway and its inactivation is known to be associated with progression and metastasis of various cancers. LATS1/2 (large tumour suppressor homolog 1 and 2), YAP1 (Yes-associated protein 1), and TEAD4 (TEA domain-containing sequence-specific transcription factors 4) are core components of the Hippo pathway, and their prognostic roles have not yet been studied in advanced gastric cancers (AGCs). A total of 318 surgically resected AGCs were retrieved. Immunolabelling for LATS1/2, YAP1 and TEAD4 was compared with clinicopathological factors including patients' survival. High expression of YAP1 and TEAD4 was identified in 108 (34.0%) and 131 (41.2%) cases, respectively, and 223 (70.1%) cases were negative for LATS1/2 expression. High YAP1 expression was significantly correlated with the presence of perineural invasion (p=0.032). High YAP1 and high TEAD4 expressions were significantly associated with poor overall survival (p<0.001 and p=0.003, respectively), and negative LATS1/2 expression was also associated with poor overall survival (p=0.002). Combined expression of YAP1

Sun Z, Zhang A, Zhang L
Inhibition of microRNA‑492 attenuates cell proliferation and invasion in retinoblastoma via directly targeting LATS2.
Mol Med Rep. 2019; 19(3):1965-1971 [PubMed] Related Publications
Numerous studies have demonstrated that microRNAs (miRNAs) are upregulated or downregulated in retinoblastoma (RB), and that this phenomenon is associated with the modulation of various malignant behaviours during RB occurrence and development. Therefore, the mechanisms that associate deregulated miRNAs with RB initiation and progression must be understood to identify effective therapeutic techniques for patients with RB. In the present study, miR‑492 expression was upregulated in RB tissues and cell lines. The effects of miR‑492 inhibition on the proliferation and invasion of RB cells were examined using Cell Counting kit‑8 and invasion assays. The results revealed that miR‑492 downregulation significantly decreased the proliferation and invasion of RB cells. Bioinformatics analysis predicted that large tumour‑suppressor kinase 2 (LATS2) was a putative target of miR‑492. Luciferase reporter assay, reverse transcription‑quantitative polymerase chain reaction and western blot analysis demonstrated that LATS2 was a direct target gene of miR‑492 in RB cells. In addition, LATS2 expression was downregulated in RB tissues, and its downregulation was inversely correlated with miR‑492 level. Furthermore, LATS2‑knockdown abrogated the effects of miR‑492 downregulation in RB cells. In conclusion, miR‑492 inhibition may impede the malignant behaviour of RB by directly targeting LATS2. Therefore, targeting this miRNA may be an effective therapeutic method for treating patients with RB.

Han LL, Yin XR, Zhang SQ
miR-650 Promotes the Metastasis and Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Directly Inhibiting LATS2 Expression.
Cell Physiol Biochem. 2018; 51(3):1179-1192 [PubMed] Related Publications
BACKGROUND/AIMS: Previous studies have confirmed that microRNAs are involved in the metastasis and epithelial-mesenchymal transition (EMT) of malignancies. In this study, we examined whether miR-650 promotes the migration, invasion, and EMT of hepatocellular carcinoma (HCC) cells by targeting the large tumor suppressor kinase 2 gene (LATS2).
METHODS: qRT-PCR was used to detect expression of miR-650 in HCC tissues and paired normal tissues. MTT and Transwell assay were used to observe the effect of miR-650 on proliferation, migration and invasion of HCC cells. Western blot assay and Immunohistochemistry were performed to demonstrate association between miR-650 expression level and epithelial-mesenchymal transition (EMT) related protein. Mechanistically, Reporter luciferase assay was performed to reveal whether large tumor suppressor kinase 2 (LATS2) was a direct target of miR-650 in HCC cells.
RESULTS: We observed that miR-650 levels were largely up-regulated in HCC tissues, and that the increased expression was closely associated with the adverse clinical features of HCC patients. Additionally, the expression of LATS2, which was identified as a direct target of miR-650, can counteract the effects of miR-650 in HCC. Furthermore, we demonstrated that high miR-650 expression levels and low LATS2 expression levels in tumors may indicate a poor prognosis for HCC patients.
CONCLUSION: In conclusion, the miR-650/LATS2 pathway may serve as a novel prognostic biomarker and an attractive therapeutic target for HCC patients.

Jones RA, Franks SE, Moorehead RA
Comparative mRNA and miRNA transcriptome analysis of a mouse model of IGFIR-driven lung cancer.
PLoS One. 2018; 13(11):e0206948 [PubMed] Free Access to Full Article Related Publications
Mouse models of cancer play an important role in elucidating the molecular mechanisms that contribute to tumorigenesis. The extent to which these models resemble one another and their human counterparts at the molecular level is critical in understanding tumorigenesis. In this study, we carried out a comparative gene expression analysis to generate a detailed molecular portrait of a transgenic mouse model of IGFIR-driven lung cancer. IGFIR-driven tumors displayed a strong resemblance with established mouse models of lung adenocarcinoma, particularly EGFR-driven models highlighted by elevated levels of the EGFR ligands Ereg and Areg. Cross-species analysis revealed a shared increase in human lung adenocarcinoma markers including Nkx2.1 and Napsa as well as alterations in a subset of genes with oncogenic and tumor suppressive properties such as Aurka, Ret, Klf4 and Lats2. Integrated miRNA and mRNA analysis in IGFIR-driven tumors identified interaction pairs with roles in ErbB signaling while cross-species analysis revealed coordinated expression of a subset of conserved miRNAs and their targets including miR-21-5p (Reck, Timp3 and Tgfbr3). Overall, these findings support the use of SPC-IGFIR mice as a model of human lung adenocarcinoma and provide a comprehensive knowledge base to dissect the molecular pathogenesis of tumor initiation and progression.

An Y, Zhang Q, Li X, et al.
Upregulated microRNA miR-21 promotes the progression of lung adenocarcinoma through inhibition of KIBRA and the Hippo signaling pathway.
Biomed Pharmacother. 2018; 108:1845-1855 [PubMed] Related Publications
PURPOSE: In this study, we aimed to identify the key pathways and hub genes in lung adenocarcinoma (LAD)
METHODS: Through gene set enrichment analysis (GSEA), the enriched KEGG pathways involved in LAD were identified. Weighted correlation network analysis (WGCNA) was employed to screen out hub genes. The differentially expressed miRNAs related to the hub gene were then screened by the network analysis. The mRNA expression levels of miR-21 and KIBRA were detected by qRT-PCR. The protein expression levels of KIBRA and the pathway related proteins LATS2 and YAP were determined by Western blot assay. The target relationship between miR-21 and KIBRA was confirmed by the dual luciferase reporter assay. Through colony formation assay, the viability of the LAD cells was determined. In addition, the mobility of LAD cells was detected by wound healing assays, and flow cytometry was employed to detect apoptotic cancer cells.
RESULTS: The hub gene identified in the black module was KIBRA, and suppression of the Hippo signaling pathway was detected in LAD. KIBRA was downregulated and miR-21 was upregulated in LAD tissues and cells; moreover, miR-21 was found to target KIBRA. KIBRA reduced the proliferative and invasive ability of LAD cells and induced apoptosis. KIBRA also activated the Hippo signaling pathway in LAD. The role of MiR-21 was opposite that of KIBRA in LAD.
CONCLUSION: MiR-21 suppressed the Hippo signaling pathway and promoted the progression of LAD through targeting KIBRA.

Shi X, Liu Z, Liu Z, et al.
Long noncoding RNA PCAT6 functions as an oncogene by binding to EZH2 and suppressing LATS2 in non-small-cell lung cancer.
EBioMedicine. 2018; 37:177-187 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: NSCLC (non-small-cell lung cancer) is the leading cause of cancer-related mortality worldwide. Both epigenetic and genetic changes contribute to the initiation, development and metastasis of NSCLC. Recently, accumulating data have begun to support the notion that long noncoding RNAs (lncRNAs) function as new crucial regulators of diverse biological processes, including proliferation, apoptosis and metastasis, and play crucial roles in tumorigenesis. Nevertheless, further study is warranted to comprehensively determine lncRNAs' functions and potential mechanism.
METHODS: In this study, we performed a comprehensive analysis of the lncRNA expression profile of NSCLC using data from TCGA and Gene Expression Omnibus (GEO). PCAT6 expression level in a cohort of 60 pairs of NSCLC tissues using quantitative real-time PCR (qRT-PCR). Additionally, Loss-of-function assays and gain-of-function assays were used to assess the role of PCAT6 in promoting NSCLC progression. Tumor formation assay in a nude mouse model was performed to verity the role of PCAT6 in NSCLC in vivo. Meanwhile, RIP, ChIP, resue experiment and western blot assays were used to highlights the potential molecular mechanism of PCAT6 in NSCLC.
FINDINGS: We identified that an oncogene, PCAT6, was upregulated in NSCLC, and this upregulation was verified in a cohort of 60 pairs of NSCLC tissues. Additionally, the expression level of PCAT6 was correlated with tumor size (P = .036), lymph node metastasis (P = .029) and TNM stage (P = .038). Loss-of-function and gain-of-function assays were used to assess the role of PCAT6 in promoting NSCLC progression. The results revealed that PCAT6 knockdown mitigated NSCLC cell growth by inducing G1-phase cell cycle arrest and apoptosis in vitro and in vivo. Whereas, PCAT6 overexpression could promoted tumor cell growth. Meanwhile, PCAT6 additionally promoted NSCLC cell migration and invasion. Furthermore, mechanistic investigation demonstrated that the oncogenic activity of PCAT6 is partially attributable to its repression of LATS2 via association with the epigenetic repressor EZH2 (Enhancer of zeste homolog 2). Overall, our study highlights the essential role of PCAT6 in NSCLC, suggesting that PCAT6 might be a potent therapeutic target for patients with NSCLC.

Han LL, Yin XR, Zhang SQ
miR-103 promotes the metastasis and EMT of hepatocellular carcinoma by directly inhibiting LATS2.
Int J Oncol. 2018; 53(6):2433-2444 [PubMed] Free Access to Full Article Related Publications
Improving the long‑term survival of patients with hepatocellular carcinoma (HCC) remains a challenge due to metastasis and recurrence. In this study, we demonstrate that the overexpression of miR‑103 in HCC cells promotes epithelial‑mesenchymal transition (EMT), and is associated with an enhanced metastasis and poor outcomes, as shown by western blot analysis and immunohistochemistry. Mechanistically, using reporter luciferase assay we reveal that the serine/threonine‑protein kinase, large tumor suppressor kinase 2 (LATS2), a key component of the Hippo signaling pathway, is a direct target of miR‑103 in HCC cells. Transwell assay, MTT assay and western blot analysis were performed to reveal that LATS2 can counteract the functional effects of miR‑103 on HCC metastasis, growth and EMT. The analyses of clinical data indicated that a high expression of miR‑103 correlated with a high expression of vimentin, but with a low expression of LATS2 and E‑cadherin in HCC tissues. miR‑103 also reduced yes‑associated protein (YAP) phosphorylation. On the whole, the findings of this study suggest that miR‑103 promotes HCC metastasis and EMT by directly inhibiting LATS2. Thus, targeting miR‑103/LATS2 may prove to be a promising therapeutic strategy for HCC.

Gill MK, Christova T, Zhang YY, et al.
A feed forward loop enforces YAP/TAZ signaling during tumorigenesis.
Nat Commun. 2018; 9(1):3510 [PubMed] Free Access to Full Article Related Publications
In most solid tumors, the Hippo pathway is inactivated through poorly understood mechanisms that result in the activation of the transcriptional regulators, YAP and TAZ. Here, we identify NUAK2 as a YAP/TAZ activator that directly inhibits LATS-mediated phosphorylation of YAP/TAZ and show that NUAK2 induction by YAP/TAZ and AP-1 is required for robust YAP/TAZ signaling. Pharmacological inhibition or loss of NUAK2 reduces the growth of cultured cancer cells and mammary tumors in mice. Moreover, in human patient samples, we show that NUAK2 expression is elevated in aggressive, high-grade bladder cancer and strongly correlates with a YAP/TAZ gene signature. These findings identify a positive feed forward loop in the Hippo pathway that establishes a key role for NUAK2 in enforcing the tumor-promoting activities of YAP/TAZ. Our results thus introduce a new opportunity for cancer therapeutics by delineating NUAK2 as a potential target for re-engaging the Hippo pathway.

Vo DD, Becquart C, Tran TPA, et al.
Building of neomycin-nucleobase-amino acid conjugates for the inhibition of oncogenic miRNAs biogenesis.
Org Biomol Chem. 2018; 16(34):6262-6274 [PubMed] Related Publications
MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers, thus being oncogenic. The inhibition of oncogenic miRNAs (defined as the blocking of miRNAs' production or function) would find application in the therapy of different types of cancer in which these miRNAs are implicated. In this work, we describe the design and synthesis of new small-molecule RNA ligands with the aim of inhibiting Dicer-mediated processing of oncogenic miRNAs. One of the synthesized compound (4b) composed of the aminoglycoside neomycin conjugated to an artificial nucleobase and to amino acid histidine is able to selectively decrease miR-372 levels in gastric adenocarcinoma (AGS) cells and to restore the expression of the target LATS2 protein. This activity led to the inhibition of proliferation of these cells. The study of the interactions of 4b with pre-miR-372 allowed for the elucidation of the molecular mechanism of the conjugate, thus leading to new perspectives for the design of future inhibitors.

Pan Y, Tong JHM, Lung RWM, et al.
RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer.
Mol Cancer. 2018; 17(1):102 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely unknown.
METHODS: Using array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays.
RESULTS: Integrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional studies revealed that RASAL2 promoted tumor progression in both KRAS/NRAS mutant and wild-type CRC cells. Knockdown of RASAL2 promoted YAP1 phosphorylation, cytoplasm retention and ubiquitination, therefore activating the hippo pathway through the LATS2/YAP1 axis.
CONCLUSIONS: Our findings demonstrated the roles of RASAL2 in CRC tumorigenesis as well as metastasis, and RASAL2 exerts its oncogenic property through LATS2/YAP1 axis of hippo signaling pathway in CRC.

Sadaf, Habib M, Khan MA, et al.
Hypermethylated LATS2 gene with decreased expression in female breast cancer: A case control study from North India.
Gene. 2018; 676:156-163 [PubMed] Related Publications
BACKGROUND: LATS2, a presumed tumor suppressor gene located on chromosome 13q11-12 is involved in cell growth related activity like regulation of cell cycle at G1/S. The reduced expression of LATS2 has been reported in many tumors; including tumors of Breast, which is to the best of our knowledge has not been studied in north Indian female breast cancer population.
OBJECTIVE: Here, we looked upon the expression pattern and methylation status of the LATS2 gene in north Indian female breast cancer cases to further strengthen its role as a tumor suppressor gene and more importantly as a cancer biomarker.
METHODS: mRNA expression level was determined by real time PCR in 140 Breast cancer patients, Protein expression was studied by Immunohistochemistry and Promoter methylation was studied by Methylation specific PCR. All findings were correlated with clinicopathological features.
RESULTS: LATS2 mRNA expression was remarkably downregulated in 67.85% (95/140) cases. The expression of Large Associated Tumor Suppressor 2 at protein level was also absent in 67.85% (95/140) cases. The absence of LATS2 protein strongly correlated with promoter hypermethylation where 91 out of a total of 107 hyper methylated cases showed absence of protein (91/107, 85%). The absence of LATS2 protein was strongly significant with HER2 neu status (0.01), TNM staging (0.009) and Molecular subtype (0.024).
CONCLUSION: The decreased expression in breast cancer seems to be associated with hypermethylation of LATS2 promoter regions. Further LATS2 as a tumor suppressor can be recognized as a promising Biomarker in Breast cancer pathogenesis. Though, further studies, targeting larger sets of breast cancer population are required to establish LATS2 as a promising biomarker.

Kang J, Wang J, Yao Z, et al.
Fascin induces melanoma tumorigenesis and stemness through regulating the Hippo pathway.
Cell Commun Signal. 2018; 16(1):37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Fascin is a F-actin bundling protein and its overexpression is correlated with poor prognosis and increases metastatic potential in a number of cancers. But underlying function and mechanism of fascin on tumorigenesis in melanoma remain elusive.
METHODS: The melanoma cell lines WM793 and WM39 were employed for the soft agar and sphere formation assay. Quantitative RT-PCR and Western blot were performed for identifying the gene expression at mRNA and protein levels, respectively. Co-IP and in vitro GST pulldown experiments were used to test the interaction between fascin and MST2.
RESULTS: Fascin regulates tumorigenesis and cancer cell stemness in melanoma through inhibition of the Hippo pathway kinase MST2 and the activation of transcription factor TAZ. Our data showed that fascin interacts with the kinase domain of MST2 to inhibit its homodimer formation and kinase activity. Depletion of fascin led to increase of p-LATS level and decrease of TAZ, but not YAP. We also demonstrated that fascin regulates melanoma tumorigenesis independent of its actin-bundling activity.
CONCLUSIONS: Fascin is a new regulator of the MST2-LATS-TAZ pathway and plays a critical role in melanoma tumorigenesis. Inhibition of fascin reduces melanoma tumorigenesis and stemness, and thus fascin could be a potential therapeutic target for this malignancy.

Lee SR, Jin H, Kim WT, et al.
Tristetraprolin activation by resveratrol inhibits the proliferation and metastasis of colorectal cancer cells.
Int J Oncol. 2018; 53(3):1269-1278 [PubMed] Related Publications
Resveratrol (RSV) is a polyphenolic compound that naturally occurs in grapes, peanuts and berries. Considerable research has been conducted to determine the benefits of RSV against various human cancer types. Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability and has decreased expression in human cancer. The present study investigated the biological effect of RSV on TTP gene regulation in colon cancer cells. RSV inhibited the proliferation and invasion/metastasis of HCT116 and SNU81 colon cancer cells. Furthermore, RSV induced a dose-dependent increase in TTP expression in HCT116 and SNU81 cells. The microarray experiment revealed that RSV significantly increased TTP expression by downregulating E2F transcription factor 1 (E2F1), a downstream target gene of TTP and regulated genes associated with inflammation, cell proliferation, cell death, angiogenesis and metastasis. Although TTP silencing inhibited TTP mRNA expression, the expression was subsequently restored by RSV. Small interfering RNA-induced TTP inhibition attenuated the effects of RSV on cell growth. In addition, RSV induced the mRNA-decaying activity of TTP and inhibited the relative luciferase activity of baculoviral IAP repeat containing 3 (cIAP2), large tumor suppressor kinase 2 (LATS2), E2F1, and lin‑28 homolog A (Lin28) in HCT116 and SNU81 cells. Therefore, RSV enhanced the inhibitory activity of TTP in HCT116 and SNU81 cells by negatively regulating cIAP2, E2F1, LATS2, and Lin28 expression. In conclusion, RSV suppressed the proliferation and invasion/metastasis of colon cancer cells by activating TTP.

Hou L, Xie S, Li G, et al.
IL-6 Triggers the Migration and Invasion of Oestrogen Receptor-Negative Breast Cancer Cells via Regulation of Hippo Pathways.
Basic Clin Pharmacol Toxicol. 2018; 123(5):549-557 [PubMed] Related Publications
Breast cancer is one of the major challenges for women's health. However, the role and mechanisms of interleukins (ILs) on the progression of breast cancer are not well illustrated. Our present study revealed that the expressions of IL-6 and IL-8 were significantly increased in oestrogen receptor-negative (ER-) breast cancer cells. Increased expression of IL-6 was observed in 83.9% (26/31) ER- breast cancer tissues as compared with their matched adjacent normal tissues. In vitro studies indicated that IL-6 can significantly promote the migration and invasion of ER- breast cancer cells via increasing the dephosphorylation, nuclear translocation and transcriptional activities of YAP in breast cancer cells. Knockdown of YAP can attenuate IL-6-induced migration and invasion of cancer cells, suggesting that YAP plays an essential role in IL-6-induced malignancy of breast cancer cells. Furthermore, IL-6 treatment also decreased the phosphorylation of LATS1/2. The knockdown of LATS1/2 synergistically suppressed si-IL-6-induced deactivation of YAP. Targeted inhibition of IL-6/YAP can significantly suppress the invasion of ER- breast cancer cells. Collectively, our study revealed that IL-6 can trigger the malignancy of breast cancer cells via activation of YAP signals. Targeted inhibition of IL-6/YAP might be a novel therapeutic approach for the treatment of ER- breast cancer.

Verdelli C, Forno I, Morotti A, et al.
The aberrantly expressed miR-372 partly impairs sensitivity to apoptosis in parathyroid tumor cells.
Endocr Relat Cancer. 2018; 25(7):761-771 [PubMed] Related Publications
Parathyroid tumors deregulate microRNAs belonging to the two clusters on the chromosome 19, the C19MC and miR-371-373 clusters. Here, we report that the embryonic miR-372 is aberrantly expressed in half of parathyroid adenomas (PAds) in most of atypical adenomas and carcinomas (

Choi W, Kim J, Park J, et al.
YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC.
Cancer Res. 2018; 78(12):3306-3320 [PubMed] Related Publications
YAP and TAZ play oncogenic roles in various organs, but the role of YAP/TAZ in gastric cancer remains unclear. Here, we show that YAP/TAZ activation initiates gastric tumorigenesis

Houshmand M, Yazdi N, Kazemi A, et al.
Long non-coding RNA PVT1 as a novel candidate for targeted therapy in hematologic malignancies.
Int J Biochem Cell Biol. 2018; 98:54-64 [PubMed] Related Publications
Cancerous cells show resistance to various forms of therapy, so applying up to the minute targeted therapy is crucial. For this purpose, long non-coding RNA PVT1 as shown by recent studies is an important oncogene that interacts with vital cellular signaling pathways and different proteins such as c-Myc, NOP2 and LATS2. Due to the enormous role of long non-coding RNAs in development of leukemias, we aimed to show the role of PVT1 knock-down on fate of different hematologic cell lines. owing to this matter, various experiments such as Real-time PCR, cell cycle analysis and apoptosis assay were performed. Meanwhile, proliferation rate by CFSE, protein expression of c-Myc and hTERT by western blot and flow cytometry analysis were investigated. Our results demonstrated that PVT1 knock-down results in c-Myc degradation, proliferation down-regulation, induction of apoptosis and G0/G1 arrest. Simultaneously, for the first time, we posited the relation between this oncogene with hTERT that reduced after PVT1 knock-down. Considering these results, long non-coding RNA PVT1 may be a potential option for targeted therapy in hematologic malignancies.

Marsola APZC, Simões BP, Palma LC, et al.
Expression of Hippo signaling pathway and Aurora kinase genes in chronic myeloid leukemia.
Med Oncol. 2018; 35(3):26 [PubMed] Related Publications
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from clonal expansion of hematopoietic stem cells positive for the Philadelphia chromosome. The CML pathogenesis is associated with expression of the BCR-ABL1 oncogene, which encodes the Bcr-Abl protein with tyrosine kinase activity, promoting the leukemic cell exacerbated myeloproliferation and resistance to apoptosis. CML patients are usually treated with tyrosine kinase inhibitors (TKI), but some of them acquire resistance or are refractory to TKI. Thus, it is still relevant to elucidate the CML pathogenesis and seek new therapeutic targets, such as the Hippo signaling pathway and cell cycle regulatory genes from the Aurora kinase family. The present study quantified the expression level of genes encoding components of the Hippo signaling pathway (LATS1, LATS2, YAP, and TAZ), AURKA and AURKB in CML patients at different stages of the disease, who were resistant or sensitive to imatinib mesylate therapy, and in healthy individuals. The expression levels of the target genes were correlated with the CML Sokal's prognostic score. The most striking results were the LATS2 and AURKA overexpression in CML patients, the overexpression of TAZ and AURKB in CML patients at advanced phases and TAZ in CML IM-resistant. The development of drugs and/or identification of tumor markers for the Hippo signaling pathway and the Aurora kinase family, either alone or in combination, can optimize CML treatment by enhancing the susceptibility of leukemic cells to apoptosis and leading to a better disease prognosis.

Zhang S, Wang J, Wang H, et al.
Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans.
Am J Pathol. 2018; 188(4):995-1006 [PubMed] Free Access to Full Article Related Publications
Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors.

Zhu C, Ji X, Zhang H, et al.
Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway.
J Biol Chem. 2018; 293(4):1178-1191 [PubMed] Free Access to Full Article Related Publications
The Hippo pathway plays important roles in controlling organ size and in suppressing tumorigenesis through large tumor suppressor kinase 1/2 (LATS1/2)-mediated phosphorylation of YAP/TAZ transcription co-activators. The kinase activity of LATS1/2 is regulated by phosphorylation in response to extracellular signals. Moreover, LATS2 protein levels are repressed by the ubiquitin-proteasome system in conditions such as hypoxia. However, the mechanism that removes the ubiquitin modification from LATS2 and thereby stabilizes the protein is not well understood. Here, using tandem affinity purification (TAP), we found that anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase complex, and USP9X, a deubiquitylase, specifically interact with LATS2. We also found that although APC1 co-localizes with LATS2 to intracellular vesicle structures, it does not regulate LATS2 protein levels and activity. In contrast, USP9X ablation drastically diminished LATS2 protein levels. We further demonstrated that USP9X deubiquitinates LATS2 and thus prevents LATS2 degradation by the proteasome. Furthermore, in pancreatic cancer cells, USP9X loss activated YAP and enhanced the oncogenic potential of the cells. In addition, the tumorigenesis induced by the USP9X ablation depended not only on LATS2 repression, but also on YAP/TAZ activity. We conclude that USP9X is a deubiquitylase of the Hippo pathway kinase LATS2 and that the Hippo pathway functions as a downstream signaling cascade that mediates USP9X's tumor-suppressive activity.

Gao Y, Yi J, Zhang K, et al.
Downregulation of MiR-31 stimulates expression of LATS2 via the hippo pathway and promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma.
J Exp Clin Cancer Res. 2017; 36(1):161 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dysregulation of miRNAs is associated with cancer development by coordinately suppressing abundant target genes. Emerging evidence indicates that miR-31 plays a dual role in tumorigenicity. However, whether miR-31 plays as an oncogene in esophageal squamous cell carcinoma (ESCC) and the potential target molecules are still unclear. MiR-31 role in ESCC was investigated and an association of the target molecules with EMT was identified in the progression of ESCC.
METHODS: Western blot assays and qRT-PCR was performed to detect the protein and mRNA levels. We investigated the role of miR-31 in the regulation of LATS2 expression in ESCC cell lines via functional assays both in vivo and in vitro. The luciferase reporter assays was conducted to confirm LATS2 is a potential target of miR-31. Immunohistochemistry was used to measure LATS2 and TAZ expression in normal and ESCC tissue.
RESULTS: LATS2 is a component of the Hippo tumor-suppressive signaling pathway. Frequent loss of heterozygosity of LATS2 has been reported in esophageal cancer. We analyzed the reciprocal expression regulation of miR-31 and LATS2 and demonstrated that LATS2 expression was elevated by down-regulation of miR-31 at the post-transcriptional level in ESCC. Moreover, miR-31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3'-UTR, a key molecule in the Hippo pathway. Then, LATS2 consequently promoted the translocation of TAZ, which was examined using immunohistochemistry. Silencing of miR-31 significantly inhibited the cell proliferation, induced apoptosis and decreased the ability of migration/invasion in vitro. LATS2 impedes ESCC cell proliferation and invasion by suppressing miR-31, as well as mice xenograft model in vivo. Meanwhile, the nuclear localization of LATS2 constrained the phosphorylation of TAZ. Then, the expression level of TAZ was notably heightened with a high risk of recurrence compared to that observed in the low-risk patients, as well as, the higher expression associated with a poor survival.
CONCLUSIONS: Our study demonstrated that overexpression of miR-31 undertook an oncogenic role in ESCC by repressing expression of LATS2 via the Hippo Pathway and activating epithelial-mesenchymal transition. LATS2 and TAZ could be potential novel molecular markers for predicting the risk of recurrence and prognosis of ESCC.

Liu Y, Lu J, Zhang Z, et al.
Amlexanox, a selective inhibitor of IKBKE, generates anti-tumoral effects by disrupting the Hippo pathway in human glioblastoma cell lines.
Cell Death Dis. 2017; 8(8):e3022 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most prevalent form of malignant brain tumor. Amlexanox, a novel compound, has been shown to have anti-cancer potential. In this study, the anti-tumoral effects and the underlying mechanisms of amlexanox were investigated. Amlexanox significantly suppressed proliferation and invasion and induced apoptosis in glioblastoma cells. Furthermore, we found that amlexanox altered the protein expression of the Hippo pathway by downregulating IKBKE. Our data indicates that IKBKE directly targets LATS1/2 and induces degradation of LATS1/2, thereby inhibiting the activity of the Hippo pathway. In vivo results further confirmed the tumor inhibitory effect of amlexanox via the downregulation of IKBKE, and amlexanox induced no apparent toxicity. Collectively, our studies suggest that amlexanox is a promising therapeutic agent for the treatment of GBM.

Li L, Zhao J, Huang S, et al.
MiR-93-5p promotes gastric cancer-cell progression via inactivation of the Hippo signaling pathway.
Gene. 2018; 641:240-247 [PubMed] Related Publications
MiR-93-5p has been previously found to be associated with gastric cancer (GC) tumorigenesis; however, the current understanding of its function in this context remains largely incomplete. In the present study, we showed that miR-93-5p was upregulated in GC tissues. We also demonstrated that miR-93-5p overexpression promoted the proliferation, migration, invasion, and chemoresistance of SGC-7901 cells in vitro, and conversely, that endogenously silencing miR-93-5p expression induced the opposite effects in HGC-27 cells. Overexpression of miR-93-5p was found to inactivate the Hippo pathway, and furthermore, miR-93-5p knockdown activated Hippo signaling. MiR-93-5p upregulation was also shown to inhibit the expression of two well-characterized Hippo pathway regulators, protocadherin Fat 4 (FAT4), and large tumor suppressors 2 (LATS2), at both the mRNA and protein level. Additionally, the results of bioinformatics analyses and luciferase reporter assays indicated that miR-93-5p directly targets the 3'-UTR of FAT4 and LATS2. Taken together, these results demonstrate that miR-93-5p promotes GC-cell progression via the inactivation of the Hippo signaling pathway, and thus, represents a potential therapeutic target for the treatment of GC.

Liu J, Ye L, Li Q, et al.
Synaptopodin-2 suppresses metastasis of triple-negative breast cancer via inhibition of YAP/TAZ activity.
J Pathol. 2018; 244(1):71-83 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, with a high incidence of distant metastasis; however, the underlying mechanism for this frequent recurrence remains unclear. Herein, we show that synaptopodin-2 (SYNPO2), a putative tumour suppressor in aggressive cancer, is frequently downregulated in TNBC by methylation of the promoter of SYNPO2. Low expression levels of SYNPO2 correlated significantly with 5-year metastatic relapse, and predicted poorer prognosis in breast cancer patients. Reintroduction of SYNPO2 inhibited the invasion and spontaneous metastasis of TNBC cells in vivo. Strikingly, downregulation of SYNPO2 is essential for the maintenance of stem cell-like properties in TNBC cells, leading to efficient distant colonization and metastasis outgrowth. Moreover, we demonstrate that SYNPO2 inhibits the activities of YAP and TAZ by stabilizing LATS2 protein, and transduction of YAP-S127A abrogates the repressive role of SYNPO2 in metastasis. Finally, immunohistochemical (IHC) analysis of breast cancer patient specimens indicated that the SYNPO2-LATS2-YAP axis is clinically relevant. These findings uncover a suppressive role of SYNPO2 in TNBC metastasis via inhibition of YAP/TAZ, and suggest that SYNPO2 might provide a potential prognosis marker and novel therapeutic strategy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Xing W, Li M, Zhang F, et al.
The conformation change and tumor suppressor role of Merlin are both independent of Serine 518 phosphorylation.
Biochem Biophys Res Commun. 2017; 493(1):46-51 [PubMed] Related Publications
Merlin functions as a tumor suppressor and suppresses malignant activity of cancer cells through multiple mechanisms. However, whether Serine 518 phosphorylation regulates the conformation of Merlin as well as the open-closed conformational changes affect Merlin's tumor inhibitory activity remain controversial. In this study, we used different mutants to mimic related conformational states of Merlin and investigated its physiological functions. Our results showed that the phosphorylation at Serine 518 has no influence on Merlin's conformation, subcellular localization, or cell proliferation inhibitory activity. As a fully closed conformational state, the A585W mutant loses the ability to recruit Lats2 to the cell membrane, but it does not affect its subcellular distribution or cell proliferation inhibitory activity. As a fully open conformational state, mimicking the conformation of Merlin isoform II, the ΔEL mutant has the same physiological function as the wild type Merlin isoform I. Collectively, we provide for the first time in vivo evidence that the function of Merlin, as a tumor suppressor is independent of its conformational change.

Zhang Y, Yan S, Chen J, et al.
WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma.
J Cell Mol Med. 2017; 21(12):3718-3729 [PubMed] Free Access to Full Article Related Publications
WWC family proteins negatively regulate HEK293 cell proliferation and organ growth by suppressing the transcriptional activity of Yes-associated protein (YAP), a major effector of the Hippo pathway. The function of the scaffolding protein WWC1 (also called KIBRA) has been intensively studied in cells and animal models. However, the expression and clinicopathologic significance of WWC2 in cancer are poorly characterized. This study aimed to clarify the biological function and mechanism of action of WWC2 in hepatocellular carcinoma (HCC). Retrospective analysis revealed WWC2 was significantly down-regulated in 95 clinical HCC tissues compared to the paired adjacent non-cancerous tissues. Moreover, loss of WWC2 expression was significantly associated with advanced clinicopathological features, including venous infiltration, larger tumour size and advanced TNM stage. Positive WWC2 expression was associated with significantly better 5-year overall survival, and WWC2 was an independent prognostic factor for overall survival in HCC. Moreover, we confirmed WWC2 inhibits HCC cell invasive ability in vitro. Elevated YAP expression was also observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated WWC2 expression correlated inversely with nuclear YAP protein expression in HCC. Mechanistically, we confirmed overexpression of WWC2 suppresses the invasive and metastatic potential of HCC cells by activating large tumour suppressor 1 and 2 kinases (LATS1/2), which in turn phosphorylates the transcriptional co-activator YAP. Overall, this study indicates WWC2 functions as a tumour suppressor by negatively regulating the Hippo signalling pathway and may serve as a prognostic marker in HCC.

Ye J, Li TS, Xu G, et al.
JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity.
Cancer Res. 2017; 77(19):5287-5300 [PubMed] Related Publications
Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting.

Guo Y, Cui J, Ji Z, et al.
miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes the development of castration resistance.
Oncogene. 2017; 36(45):6336-6347 [PubMed] Related Publications
Clinical intervention for patients with advanced prostate cancer (PCa) remains challenging due to the inevitable recurrence of castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT). Cancer stem cells (CSCs) with serial tumor-propagating capacity are considered to be the driving force for PCa progression and recurrence. In this study, we report that the miR-302/367 cluster, a previously identified potent pluripotency regulator, is upregulated in prostate tumors. Specifically, the forced expression of the miR-302/367 cluster accelerates the in vitro and in vivo growth of PCa cells and their resistance to androgen ablation, whereas the knockdown of the miR-302/367 cluster using anti-sense RNA suppresses the incidence of formation, growth rate and endpoint weight of PCa cell tumors. Mechanistically, we find that LATS2, a key component of the tumor-suppressive Hippo signaling pathway, acts as a direct target of the miR-302/367 cluster in PCa cells. The downregulation of LATS2 by the miR-302/367 cluster reduces the phosphorylation and enhances the nuclear translocation of the YAP oncoprotein. Conversely, the restoration of LATS2 expression abrogates the tumor-promoting effects of forced miR-302/367 cluster expression. Collectively, the potent pluripotency regulator-triggered miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes castration resistance. Thus, targeting this signaling axis may represent a promising therapeutic strategy for CRPC.

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