The epigenetic modifier CHD5 functions as a novel tumor suppressor for renal cell carcinoma and is predominantly inactivated by promoter CpG methylation

Zhenfang Du, Lili Li, Xin Huang, Jie Jin, Suming Huang, Qian Zhang, Qian Tao

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Renal cell carcinoma (RCC) is the most common urological cancer with steadily increasing incidence. A series of tumor suppressor genes (TSGs) have been identified methylated in RCC as potential epigenetic biomarkers. We identified a 1p36.3 TSG candidate CHD5 as a methylated target in RCC through epigenome study. As the role of CHD5 in RCC pathogenesis remains elusive, we further studied its expression and molecular functions in RCC cells. We found that CHD5 was broadly expressed in most normal genitourinary tissues including kidney, but frequently silenced or downregulated by promoter CpG methylation in 78% of RCC cell lines and 44% (24/55) of primary tumors. In addition, CHD5 mutations appear to be rare in RCC tumors through genome database mining. In methylated/silenced RCC cell lines, CHD5 expression could be restored with azacytidine demethylation treatment. Ectopic expression of CHD5 in RCC cells significantly inhibited their clonogenicity, migration and invasion. Moreover, we found that CHD5, as a chromatin remodeling factor, suppressed the expression of multiple targets including oncogenes (MYC, MDM2, STAT3, CCND1, YAP1), epigenetic master genes (Bmi-1, EZH2, JMJD2C), as well as epithelial-mesenchymal transition and stem cell markers (SNAI1, FN1, OCT4). Further chromatin immunoprecipitation (ChIP) assays confirmed the binding of CHD5 to target gene promoters. Thus, we demonstrate that CHD5 functions as a novel TSG for RCC, but is predominantly inactivated by promoter methylation in primary tumors.

Original languageEnglish (US)
Pages (from-to)21618-21630
Number of pages13
JournalOncotarget
Volume7
Issue number16
DOIs
StatePublished - Apr 19 2016

Fingerprint

Renal Cell Carcinoma
Epigenomics
Methylation
Neoplasms
Tumor Suppressor Genes
Urologic Neoplasms
Azacitidine
Cell Line
myc Genes
Chromatin Assembly and Disassembly
Epithelial-Mesenchymal Transition
Chromatin Immunoprecipitation
Mesenchymal Stromal Cells
Genes
Down-Regulation
Biomarkers
Genome
Databases
Kidney
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Du, Zhenfang ; Li, Lili ; Huang, Xin ; Jin, Jie ; Huang, Suming ; Zhang, Qian ; Tao, Qian. / The epigenetic modifier CHD5 functions as a novel tumor suppressor for renal cell carcinoma and is predominantly inactivated by promoter CpG methylation. In: Oncotarget. 2016 ; Vol. 7, No. 16. pp. 21618-21630.
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abstract = "Renal cell carcinoma (RCC) is the most common urological cancer with steadily increasing incidence. A series of tumor suppressor genes (TSGs) have been identified methylated in RCC as potential epigenetic biomarkers. We identified a 1p36.3 TSG candidate CHD5 as a methylated target in RCC through epigenome study. As the role of CHD5 in RCC pathogenesis remains elusive, we further studied its expression and molecular functions in RCC cells. We found that CHD5 was broadly expressed in most normal genitourinary tissues including kidney, but frequently silenced or downregulated by promoter CpG methylation in 78{\%} of RCC cell lines and 44{\%} (24/55) of primary tumors. In addition, CHD5 mutations appear to be rare in RCC tumors through genome database mining. In methylated/silenced RCC cell lines, CHD5 expression could be restored with azacytidine demethylation treatment. Ectopic expression of CHD5 in RCC cells significantly inhibited their clonogenicity, migration and invasion. Moreover, we found that CHD5, as a chromatin remodeling factor, suppressed the expression of multiple targets including oncogenes (MYC, MDM2, STAT3, CCND1, YAP1), epigenetic master genes (Bmi-1, EZH2, JMJD2C), as well as epithelial-mesenchymal transition and stem cell markers (SNAI1, FN1, OCT4). Further chromatin immunoprecipitation (ChIP) assays confirmed the binding of CHD5 to target gene promoters. Thus, we demonstrate that CHD5 functions as a novel TSG for RCC, but is predominantly inactivated by promoter methylation in primary tumors.",
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The epigenetic modifier CHD5 functions as a novel tumor suppressor for renal cell carcinoma and is predominantly inactivated by promoter CpG methylation. / Du, Zhenfang; Li, Lili; Huang, Xin; Jin, Jie; Huang, Suming; Zhang, Qian; Tao, Qian.

In: Oncotarget, Vol. 7, No. 16, 19.04.2016, p. 21618-21630.

Research output: Contribution to journalArticle

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AU - Du, Zhenfang

AU - Li, Lili

AU - Huang, Xin

AU - Jin, Jie

AU - Huang, Suming

AU - Zhang, Qian

AU - Tao, Qian

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