title: Epigenetic inactivation of the candidate tumor suppressor gene ASC/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target.
abstract: This study investigated the epigenetic alteration and biological function of the pro-apoptotic gene ASC/TMS1 in renal cell carcinoma. ASC/TMS1 was downregulated in five out of six RCC cell lines. A significant downregulation was also detected in sixty-seven paired renal tumors compared with adjacent non-cancerous tissues. The downregulation of ASC/TMS1 was correlated with promoter hypermethylation and could be restored with demethylation treatment. Re-expression of ASC/TMS1 in silenced RCC cell lines inhibited cell viability, colony formation, arrested cell cycle, induced apoptosis, suppressed cell invasion and repressed tumorigenicity in SCID mice. The antitumorigenic function of ASC/TMS1 in renal cancer was partially regulated by activation of p53 and p21 signaling. In addition, restoration of ASC/TMS1 sensitizes RCC cells to DNA damaging agents. Knockdown of ASC/TMS1 reduced DNA damaging agents-induced p53 activation and cell apoptosis. Moreover, ASC/TMS1 hypermethylation was further detected in 41.1% (83/202) of RCC tumors, but only 12% in adjacent non-cancerous tissues. ASC/TMS1 methylation was significantly correlated with higher tumor nuclear grade. In conclusion, ASC/TMS1 is a novel functional tumor suppressor in renal carcinogenesis. ASC/TMS1 tumor specific methylation may be a useful biomarker for designing improved diagnostic and therapeutic strategies for RCC.
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Qianling
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Mengkui
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053468:CARD Signaling Adaptor Proteins; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D015398:Signal Transduction
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C402202:PYCARD protein, human
keywords: ASC/TMS1; DNA methylation; chemosensitivity; renal cell carcinoma; tumor suppressor