Gene Summary

Gene:DNAJB4; DnaJ heat shock protein family (Hsp40) member B4
Aliases: DjB4, HLJ1, DNAJW
Summary:The protein encoded by this gene is a molecular chaperone, tumor suppressor, and member of the heat shock protein-40 family. The encoded protein binds the cell adhesion protein E-cadherin and targets it to the plasma membrane. This protein also binds incorrectly folded E-cadherin and targets it for endoplasmic reticulum-associated degradation. This gene is a strong tumor suppressor for colorectal carcinoma, and downregulation of it may serve as a good biomarker for predicting patient outcomes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:dnaJ homolog subfamily B member 4
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • Gene Enhancer Elements
  • src-Family Kinases
  • Non-Small Cell Lung Cancer
  • Signal Transduction
  • Stomach Cancer
  • Chromosome 1
  • Neoplasm Metastasis
  • Oligonucleotide Array Sequence Analysis
  • DNAJB4
  • Mutation
  • TFAP2A
  • HSP40 Heat-Shock Proteins
  • YY1 Transcription Factor
  • Cancer Gene Expression Regulation
  • Promoter Regions
  • Cell Movement
  • Transfection
  • siRNA
  • Cell Proliferation
  • Tumor Suppressor Gene
  • Adenocarcinoma
  • Apoptosis
  • Biomarkers, Tumor
  • Dimethyl Sulfoxide
  • Neoplasm Invasiveness
  • Liver Cancer
  • Proto-Oncogene Proteins c-jun
  • Transcriptional Activation
  • Cadherins
  • Protein Binding
  • Up-Regulation
  • Messenger RNA
  • Gene Expression
  • Transcription Factors
  • Lung Cancer
  • Tumor Suppressor Proteins
  • Molecular Sequence Data
  • Hepatocellular Carcinoma
  • Base Sequence
  • Transcription Factor AP-1
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: DNAJB4 (cancer-related)

Acun T, Doberstein N, Habermann JK, et al.
HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer.
OMICS. 2017; 21(5):257-265 [PubMed] Free Access to Full Article Related Publications
Breast cancer is the most common cancer type and cause of cancer-related mortality among women worldwide. New biomarker discovery is crucial for diagnostic innovation and personalized medicine in breast cancer. Heat shock proteins (HSPs) have been increasingly reported as biomarkers and potential drug targets for cancers. HLJ1 (DNAJB4) belongs to the DNAJ (HSP40) family of HSPs and is regarded as a tumor suppressor gene in lung, colon, and gastric cancers. However, the role of the HLJ1 gene in breast cancer is currently unknown. We evaluated the role of the HLJ1 gene in breast cancer progression by analyzing its in vitro and in vivo expression and its genetic/epigenetic alterations. HLJ1 expression was found to be reduced or lost in breast cancer cell lines (SK-BR-3, MDA-MB-231, ZR-75-1) compared with the nontumorigenic mammary epithelial cell line (MCF 10A). In a clinical context for breast cancer progression, the HLJ1 expression was significantly less frequent in invasive breast carcinoma samples (n = 230) compared with normal breast tissue (n = 100), benign neoplasia (n = 53), and ductal carcinoma in situ (n = 21). In methylation analyses by the combined bisulfite restriction analysis assay, the CpG island located in the 5'-flanking region of the HLJ1 gene was found to be methylated in breast cancer cell lines. HLJ1 expression was restored in the ZR-75-1 cell line by DNA demethylating agent 5-Aza-2'-deoxycytidine (5-AzadC) and histone deacetylase inhibitor trichostatin A. These new observations support the idea that HLJ1 is a tumor suppressor candidate and potential biomarker for breast cancer. Epigenomic mechanisms such as CpG methylation and histone deacetylation might contribute to downregulation of HLJ1 expression. We call for future functional, epigenomic, and clinical studies to ascertain the contribution of HLJ1 to breast cancer pathogenesis and, importantly, evaluate its potential for biomarker development in support of personalized medicine diagnostic innovation in clinical oncology.

Chen CH, Chang WH, Su KY, et al.
HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms.
Oncogene. 2016; 35(43):5674-5685 [PubMed] Related Publications
HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1-Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1-Src complex might provide a promising molecular model for developing new anticancer strategies.

Ozgur A, Tutar L, Tutar Y
Regulation of Heat Shock Proteins by miRNAs in human breast cancer.
Microrna. 2014; 3(2):118-35 [PubMed] Related Publications
Metabolic rates of cancer cells are faster compared to normal cells. This faster rate yields aberrant protein folding and causes loss of protein function. Therefore, cancer cells need more Heat Shock Proteins (HSPs) for proper substrate- protein folding on oncogenic pathways. Pseudogenes regulate tumor suppressors and oncogenes, and pseudogenes are deregulated in cancer progression. Further, alterations in miRNA expression have been identified in different cancer types. MiRNAs also have both oncogenic and tumour-suppressive roles in breast cancer post-transcriptional gene regulation. Breast cancer is a genetic disease and we performed miRNA analysis in human breast cancer cell lines to identify miRNAs in association with HSPs and pseudogenes by employing CellMiner; a web-based suite. CellMiner integrates several databases and help analysing microarray metadata. The experimental data provide a platform for researchers to compare macromolecules' relationships in NCI-60 cell lines. Breast cancer associated miRNAs gathered from literature and analyzed by employing this suite, significantly correlated HSP genes and pseudogenes in the breast cancer are determined as; HSPA13, HSP90AB1, TRAP1, HSPB1, DNAJB4, HSPD1 and HSP90AA4P, HSPB1P1, DNAJC8P1, HSPD1P9 respectively. HSPs involved in breast cancer are regulated by several miRNAs and miRNA regulators from CellMiner data found as hsa-miR-17, hsa-miR-22, hsa-miR-93, hsa-miR-106a, hsa-miR-125b, hsa-miR-130a, and hsamiR- 141. Cross check of the determined miRNAs and target HSPs was performed by target site prediction software. Comparison of the experimental data from CellMiner and software predicted data indicate differences. CellMiner data provide a vast miRNA types compared to prediction softwares-web tools data and reported miRNAs in the literature. Therefore, reported key miRNAs in this work that are not studied earlier may help cancer researchers to uncover novel posttranslational regulation mechanisms. Cancer cells use HSP network as an escape mechanism from apoptosis, therefore inhibition of associated HSPs by modulating miRNAs may provide a novel therapy for the tumorigenesis.

Davis AL, Qiao S, Lesson JL, et al.
The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells.
J Biol Chem. 2015; 290(3):1623-38 [PubMed] Free Access to Full Article Related Publications
Pharmacological induction of proteotoxic stress is rapidly emerging as a promising strategy for cancer cell-directed chemotherapeutic intervention. Here, we describe the identification of a novel drug-like heat shock response inducer for the therapeutic induction of proteotoxic stress targeting malignant human melanoma cells. Screening a focused library of compounds containing redox-directed electrophilic pharmacophores employing the Stress & Toxicity PathwayFinder(TM) PCR Array technology as a discovery tool, a drug-like triphenylmethane-derivative (aurin; 4-[bis(p-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one) was identified as an experimental cell stress modulator that causes (i) heat shock factor transcriptional activation, (ii) up-regulation of heat shock response gene expression (HSPA6, HSPA1A, DNAJB4, HMOX1), (iii) early unfolded protein response signaling (phospho-PERK, phospho-eIF2α, CHOP (CCAAT/enhancer-binding protein homologous protein)), (iv) proteasome impairment with increased protein-ubiquitination, and (v) oxidative stress with glutathione depletion. Fluorescence polarization-based experiments revealed that aurin displays activity as a geldanamycin-competitive Hsp90α-antagonist, a finding further substantiated by molecular docking and ATPase inhibition analysis. Aurin exposure caused caspase-dependent cell death in a panel of human malignant melanoma cells (A375, G361, LOX-IMVI) but not in non-malignant human skin cells (Hs27 fibroblasts, HaCaT keratinocytes, primary melanocytes) undergoing the aurin-induced heat shock response without impairment of viability. Aurin-induced melanoma cell apoptosis depends on Noxa up-regulation as confirmed by siRNA rescue experiments demonstrating that siPMAIP1-based target down-regulation suppresses aurin-induced cell death. Taken together, our data suggest feasibility of apoptotic elimination of malignant melanoma cells using the quinone methide-derived heat shock response inducer aurin.

Lu Y, Wei C, Xi Z
Curcumin suppresses proliferation and invasion in non-small cell lung cancer by modulation of MTA1-mediated Wnt/β-catenin pathway.
In Vitro Cell Dev Biol Anim. 2014; 50(9):840-50 [PubMed] Related Publications
Curcumin, a naturally occurring phenolic compound, has a diversity of antitumor activities. It has been previously demonstrated that curcumin can inhibit the invasion and metastasis of tumors through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). However, the specific roles and mechanisms of curcumin in regulating the malignant behaviors of non-small cell lung cancer (NSCLC) cells still remain unclear. In this study, we found that curcumin could inhibit the proliferation and invasion of NSCLC cells and induce G0/G1 phase arrest. Metastasis-associated protein 1 (MTA1) overexpression has been detected in a wide variety of aggressive tumors and plays an important role on cell invasion and metastasis. Our results showed that curcumin could effectively inhibit the MTA1 expression of NSCLC cells. Further research on the subsequent mechanism showed that curcumin inhibited the proliferation and invasion of NSCLC cells through MTA1-mediated inactivation of Wnt/β-catenin pathway. Wnt/β-catenin signaling was reported to play a critical cooperative role on promoting lung tumorigenesis. Thus, these investigations provided novel insights into the mechanisms of curcumin on inhibition of NSCLC cell growth and invasion and showed potential therapeutic strategies for NSCLC.

Lai YH, Yu SL, Chen HY, et al.
The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer.
Carcinogenesis. 2013; 34(5):1069-80 [PubMed] Related Publications
HLJ1 is a novel tumour suppressor and is a potential druggable target for non-small-cell lung cancer (NSCLC). In this report, using a promoter-containing enhancer region as the HLJ1-targeting drug-screening platform, we identified several herbal compounds from a Chinese herbal bank with the capacity to enhance HLJ1 promoter activity and suppress tumour growth and invasion of NSCLC. Among the herbal drugs identified, the andrographolide (from Andrographis paniculata [Burm. f.] Nees.) most significantly induced HLJ1 expression and suppressed tumorigenesis both in vitro and in vivo. The andrographolide upregulates HLJ1 via JunB activation, which modulates AP-2α binding at the MMP-2 promoter and represses the expression of MMP-2. In addition, silencing of HLJ1 partially reverses the inhibition of cancer-cell invasion by andrographolide. Microarray transcriptomic analysis was performed to comprehensively depict the andrographolide-regulated signalling pathways. We showed that andrographolide can affect 939 genes (analysis of variance, false discovery rate < 0.05) that are dominantly involved in the cell cycle, apoptosis and adhesion-related biological signalling, including mitogen-activated protein kinase, focal adhesion and tight junction pathways, indicating the diverse effects of andrographolide on anticancer invasion and proliferation. In conclusion, the HLJ1-targeting drug-screening platform is useful for screening of novel anticancer compounds. Using this platform, we identified andrographolide is a promising new anticancer agent that could suppress tumour growth and invasion in NSCLC.

Wang CC, Lin SY, Lai YH, et al.
Dimethyl sulfoxide promotes the multiple functions of the tumor suppressor HLJ1 through activator protein-1 activation in NSCLC cells.
PLoS One. 2012; 7(4):e33772 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dimethyl sulfoxide (DMSO) is an amphipathic molecule that displays a diversity of antitumor activities. Previous studies have demonstrated that DMSO can modulate AP-1 activity and lead to cell cycle arrest at the G1 phase. HLJ1 is a newly identified tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. Its transcriptional activity is regulated by the transcription factor AP-1. However, the effects of DMSO on HLJ1 are still unknown. In the present study, we investigate the antitumor effects of DMSO through HLJ1 induction and demonstrate the mechanisms involved.
METHODS AND FINDINGS: Low-HLJ1-expressing highly invasive CL1-5 lung adenocarcinoma cells were treated with various concentrations of DMSO. We found that DMSO can significantly inhibit cancer cell invasion, migration, proliferation, and colony formation capabilities through upregulation of HLJ1 in a concentration-dependent manner, whereas ethanol has no effect. In addition, the HLJ1 promoter and enhancer reporter assay revealed that DMSO transcriptionally upregulates HLJ1 expression through an AP-1 site within the HLJ1 enhancer. The AP-1 subfamily members JunD and JunB were significantly upregulated by DMSO in a concentration-dependent manner. Furthermore, pretreatment with DMSO led to a significant increase in the percentage of UV-induced apoptotic cells.
CONCLUSIONS: Our results suggest that DMSO may be an important stimulator of the tumor suppressor protein HLJ1 through AP-1 activation in highly invasive lung adenocarcinoma cells. Targeted induction of HLJ1 represents a promising approach for cancer therapy, which also implied that DMSO may serve as a potential lead compound or coordinated ligand for the development of novel anticancer drugs.

Qiao S, Lamore SD, Cabello CM, et al.
Thiostrepton is an inducer of oxidative and proteotoxic stress that impairs viability of human melanoma cells but not primary melanocytes.
Biochem Pharmacol. 2012; 83(9):1229-40 [PubMed] Free Access to Full Article Related Publications
Pharmacological induction of oxidative and proteotoxic stress has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Guided by a differential phenotypic drug screen for novel lead compounds that selectively induce melanoma cell apoptosis without compromising viability of primary human melanocytes, we have focused on the cyclic pyridinyl-polythiazolyl peptide-antimicrobial thiostrepton. Using comparative gene expression-array analysis, the early cellular stress response induced by thiostrepton was examined in human A375 metastatic melanoma cells and primary melanocytes. Thiostrepton displayed selective antimelanoma activity causing early induction of proteotoxic stress with massive upregulation of heat shock (HSPA6, HSPA1A, DNAJB4, HSPB1, HSPH1, HSPA1L, CRYAB, HSPA5, DNAJA1), oxidative stress (HMOX1, GSR, SOD1), and ER stress response (DDIT3) gene expression, confirmed by immunodetection (Hsp70, Hsp70B', HO-1, phospho-eIF2α). Moreover, upregulation of p53, proapoptotic modulation of Bcl-2 family members (Bax, Noxa, Mcl-1, Bcl-2), and induction of apoptotic cell death were observed. Thiostrepton rapidly induced cellular oxidative stress followed by inactivation of chymotrypsin-like proteasomal activity and melanoma cell-directed accumulation of ubiquitinated proteins, not observed in melanocytes that were resistant to thiostrepton-induced apoptosis. Proteotoxic and apoptogenic effects were fully antagonized by antioxidant intervention. In RPMI 8226 multiple myeloma cells, known to be exquisitely sensitive to proteasome inhibition, early proteotoxic and apoptogenic effects of thiostrepton were confirmed by array analysis indicating pronounced upregulation of heat shock response gene expression. Our findings demonstrate that thiostrepton displays dual activity as a selective prooxidant and proteotoxic chemotherapeutic, suggesting feasibility of experimental intervention targeting metastatic melanoma and other malignancies including multiple myeloma.

Zhang L, Cai X, Chen K, et al.
Hepatitis B virus protein up-regulated HLJ1 expression via the transcription factor YY1 in human hepatocarcinoma cells.
Virus Res. 2011; 157(1):76-81 [PubMed] Related Publications
The hepatitis B virus (HBV) protein plays a major role in hepatocellular carcinoma (HCC) development. However, its contribution to tumor invasion and metastasis has not been established so far. HLJ1 was recently cloned and classified as a member of the heat shock protein 40 family (Hsp40/DnaJ) which is abundantly expressed in HBV-related tumors, might be involved in tumor progression. In this study, the role of HBV in activation of HLJ1 was investigated. In HepG2 cells with transit or stable expression of HBV, HLJ1 expression was activated by HBV. The activity assay of HLJ1 promoter revealed that HBV up-regulated HLJ1 expression through the transcription factor YY1 sites within the HLJ1 promoter. YY1 expression was significantly up-regulated by HBV in a concentration-dependent manner. Knockdown of YY1 expression could partially reduce the HBV-induced HLJ1 activation which indicated that YY1 would be involved in HBV-induced HLJ1 expression. In conclusion, our data showed that HBV could promote HLJ1 expression by up-regulating the transcription factor YY1, and this provided a new insight of the mechanism of HBV induction in tumor metastasis.

Chen CH, Lin H, Chuang SM, et al.
Acidic stress facilitates tyrosine phosphorylation of HLJ1 to associate with actin cytoskeleton in lung cancer cells.
Exp Cell Res. 2010; 316(17):2910-21 [PubMed] Related Publications
Acidosis is a common stress in solid tumours and is also a major determinant of tumour growth, metabolism, and metastasis. During cellular stress, heat shock proteins play an important role in actin cytoskeleton stability. HLJ1, a member of the DnaJ-like heat shock protein 40, has been characterised as a tumour suppressor gene; however, the effect of acidic stress on HLJ1 is unknown. In this study, we found that the migration ability of human lung adenocarcinoma cells was significantly impaired following the increased protein level of HLJ1 under acidic culture conditions. However, HLJ1 transcriptional activity was no different in the normal and acidic culture medium. Incubation of the cells in an acidic extracellular pH (pHe 6.4) caused up-regulated tyrosine phosphorylation of HLJ1 within 2h. We further identified the sub-cellular distribution of tyrosine phospho-HLJ1 and its tyrosine-phosphorylated sites. Most importantly, acidic stress was observed to remarkably enhance the interaction between HLJ1 and β-actin, which was a tyrosine phosphorylation-dependent association. In conclusion, our results not only validate that HLJ1 is a tyrosine phosphoprotein, but also suggest that the increased level of tyrosine phospho-HLJ1 is crucial for binding with the actin cytoskeleton, especially in acidic pHe. We propose that acidic stress increases the association between HLJ1 and β-actin to modulate migration of human lung cancer cells.

Chang TP, Yu SL, Lin SY, et al.
Tumor suppressor HLJ1 binds and functionally alters nucleophosmin via activating enhancer binding protein 2alpha complex formation.
Cancer Res. 2010; 70(4):1656-67 [PubMed] Related Publications
HLJ1, a member of the heat shock protein 40 chaperone family, is a newly identified tumor suppressor that has been implicated in tumorigenesis and metastasis in non-small cell lung cancer. However, the mechanism of HLJ1 action is presently obscure. In this study, we report that HLJ1 specifically interacts with the nuclear protein nucleophosmin (NPM1), forming a multiprotein complex that alters the nucleolar distribution and oligomerization state of NPM1. Enforced accumulation of NPM1 oligomers by overexpression in weakly invasive but high HLJ1-expressing cells induced the activity of signal transducer and activator of transcription 3 (STAT3) and increased cellular migration, invasiveness, and colony formation. Furthermore, silencing HLJ1 accelerated NPM1 oligomerization, inhibited the activity of transcription corepressor activating enhancer binding protein 2alpha (AP-2alpha), and increased the activities of matrix metalloproteinase-2 (MMP-2) and STAT3. Our findings suggest that HLJ1 switches the role of NPM1, which can act as tumor suppressor or oncogene, by modulating the oligomerization of NPM1 via HLJ1-NPM1 heterodimer formation and recruiting AP-2alpha to the MMP-2 promoter.

Wang CC, Tsai MF, Dai TH, et al.
Synergistic activation of the tumor suppressor, HLJ1, by the transcription factors YY1 and activator protein 1.
Cancer Res. 2007; 67(10):4816-26 [PubMed] Related Publications
HLJ1 is a novel tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. However, the mechanism of HLJ1 activation is currently unclear. Here, we identify an enhancer segment in the HLJ1 gene at -2,125 to -1,039 bp upstream of the transcription start site. A 50-bp element between -1,492 and -1,443 bp is the minimal enhancer segment, which includes the activator protein 1 (AP-1) site (-1,457 to -1,451 bp), an essential regulatory domain that binds the transcriptional factors FosB, JunB, and JunD. Chromatin immunoprecipitation assays confirm that these AP-1 family members bind to a specific site in the HLJ1 enhancer segment in vivo. Overexpression of either YY1 at promoter or AP-1 at enhancer results in a 3-fold increase in the transcriptional activity of HLJ1. We propose a novel mechanism whereby expression of the tumor suppressor, HLJ1, is up-regulated via enhancer AP-1 binding to promoter YY1 and the coactivator, p300, through DNA bending and multiprotein complex formation. The combined expression of AP-1 and YY1 enhances HLJ1 expression by more than five times and inhibits in vitro cancer cell invasion. Elucidation of the regulatory mechanism of HLJ1 expression may facilitate the development of personalized therapy by inhibiting cancer cell proliferation, angiogenesis, and metastasis.

Tsai MF, Wang CC, Chang GC, et al.
A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma.
J Natl Cancer Inst. 2006; 98(12):825-38 [PubMed] Related Publications
BACKGROUND: We previously identified DnaJ-like heat shock protein (HLJ1) as a gene associated with tumor invasion. Here, we investigated the clinical significance of HLJ1 expression in non-small-cell lung cancer (NSCLC) patients and its role in cancer progression.
METHODS: We induced HLJ1 overexpression or knockdown in human lung adenocarcinoma CL1-5 cells and analyzed cell proliferation, anchorage-independent growth, in vivo tumorigenesis, cell motility, invasion, and cell cycle progression. Expression of genes that act downstream of HLJ1 was examined by DNA microarray analysis, pathway analysis, and western blotting. We measured HLJ1 expression in tumors and adjacent normal tissues of 71 NSCLC patients by quantitative reverse transcription-polymerase chain reaction. Associations between HLJ1 expression and disease-free and overall survival were determined using the log-rank test and multivariable Cox proportional hazards regression analysis. Validation was performed in an independent cohort of 56 NSCLC patients. Loss of heterozygosity (LOH) mapping of the HLJ1 locus was analyzed in 48 paired microdissected NSCLC tumors. All statistical tests were two-sided.
RESULTS: HLJ1 expression inhibited lung cancer cell proliferation, anchorage-independent growth, tumorigenesis, cell motility, and invasion, and slowed cell cycle progression through a novel STAT1/P21(WAF1) pathway that is independent of P53 and interferon. HLJ1 expression was lower in tumors than in adjacent normal tissue in 55 of 71 patients studied. NSCLC patients with high HLJI expressing tumors had reduced cancer recurrence (hazard ratio [HR] = 0.47; 95% confidence interval [CI] = 0.23 to 0.93; P = .03) and longer overall survival (HR = 0.38; 95% CI = 0.16 to 0.89; P = .03) than those with low-expressing tumors. Validation in the independent patient cohort confirmed the association between HLJ1 expression and patient outcome. LOH mapping revealed high frequencies (66.7% and 70.8%) of allelic loss and microsatellite instability (87.5% and 95.2%) of the HLJ1 locus at chromosome 1p31.1.
CONCLUSIONS: HLJ1 is a novel tumor suppressor in NSCLC, and high HLJ1 expression is associated with reduced cancer recurrence and prolonged survival of NSCLC patients.

Wang CC, Tsai MF, Hong TM, et al.
The transcriptional factor YY1 upregulates the novel invasion suppressor HLJ1 expression and inhibits cancer cell invasion.
Oncogene. 2005; 24(25):4081-93 [PubMed] Related Publications
By using microarray and an invasion/metastasis lung cell line model, we identified the DnaJ-like heat shock protein 40, HLJ1, and found that the expression of HLJ1 correlates negatively with cancer cell invasion ability. Overexpression of HLJ1 can suppress cancer cell invasion in vitro. We further characterize the putative promoter region and investigate the transcriptional regulations of human HLJ1. A serial deletion of the 1.2 kb at the 5'-flanking region of the human HLJ1 gene was subcloned into a vector containing reporter gene and transfected into human lung adenocarcinoma cell line CL1-0, followed by luciferase activity assay. The results indicated that the region from -232 to +176 could drive the basal transcriptional activity of the HLJ1 gene. Sequence analysis of the HLJ1 gene promoter region showed absence of a TATA box, but identified an inverted CCAAT box and four YY1 transcriptional factor-binding sites, which may be important in the regulation of HLJ1 expression. Co-transfection of the YY1 and HLJ1 basal promoter regions, site-directed mutagenesis, and electrophoretic mobility shift assay confirmed that YY1 could upregulate HLJ1 basal promoter activity. Furthermore, we also demonstrated that overexpression of YY1 in CL1-0 cells can increase HLJ1 expression and reduce cell invasive capability. The reduction of cancer cell invasive ability is, at least in part, through upregulation of E-cadherin expression. The increase in HLJ1 and E-cadherin expression, as well as the suppression of invasion ability, can be reversed specifically by HLJ1 siRNA.

Katoh M
GIPC gene family (Review).
Int J Mol Med. 2002; 9(6):585-9 [PubMed] Related Publications
GIPC1/GIPC/RGS19IP1, GIPC2, and GIPC3 genes constitute the human GIPC gene family. GIPC1 and GIPC2 show 62.0% total-amino-acid identity. GIPC1 and GIPC3 show 59.9% total-amino-acid identity. GIPC2 and GIPC3 show 55.3% total-amino-acid identity. GIPCs are proteins with central PDZ domain and GIPC homology (GH1 and GH2) domains. PDZ, GH1, and GH2 domains are conserved among human GIPCs, Xenopus GIPC/Kermit, and Drosophila GIPC/ LP09416. Bioinformatics revealed that GIPC genes are linked to prostanoid receptor genes and DNAJB genes in the human genome as follows: GIPC1 gene is linked to prostaglandin E receptor 1 (PTGER1) gene and DNAJB1 gene in human chromosome 19p13.2-p13.1 region; GIPC2 gene to prostaglandin F receptor (PTGFR) gene and DNAJB4 gene in human chromosome 1p31.1-p22.3 region; GIPC3 gene to thromboxane A2 receptor (TBXA2R) gene in human chromosome 19p13.3 region. GIPC1 and GIPC2 mRNAs are expressed together in OKAJIMA, TMK1, MKN45 and KATO-III cells derived from diffuse-type of gastric cancer, and are up-regulated in several cases of primary gastric cancer. PDZ domain of GIPC family proteins interact with Frizzled-3 (FZD3) class of WNT receptor, insulin-like growth factor-I (IGF1) receptor, receptor tyrosine kinase TrkA, TGF-beta type III receptor (TGF-beta RIII), integrin alpha6A subunit, transmembrane glycoprotein 5T4, and RGS19/RGS-GAIP. Because RGS19 is a member of the RGS family that regulate heterotrimeric G-protein signaling, GIPCs might be scaffold proteins linking heterotrimeric G-proteins to seven-transmembrane-type WNT receptor or to receptor tyrosine kinases. Therefore, GIPC1, GIPC2 and GIPC3 might play key roles in carcinogenesis and embryogenesis through modulation of growth factor signaling and cell adhesion.

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Cite this page: Cotterill SJ. DNAJB4, Cancer Genetics Web: http://www.cancer-genetics.org/DNAJB4.htm Accessed:

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