title: REST-dependent expression of TRF2 renders non-neuronal cancer cells resistant to DNA damage during oxidative stress.
abstract: REST is a neuronal gene silencing factor ubiquitously expressed in non-neuronal tissues. REST is additionally believed to serve as a tumor suppressor in non-neuronal cancers. Conversely, recent findings on REST-dependent tumorigenesis in non-neuronal cells consistently suggest a potential role of REST as a tumor promoter. Here, we have uncovered for the first time the mechanism by which REST contributes to cancer cell survival in non-neuronal cancers. We observed abundant expression of REST in various types of non-neuronal cancer cells compared to normal tissues. The delicate roles of REST were further evaluated in HCT116 and HeLa, non-neuronal cancer cell lines expressing REST. REST silencing resulted in decreased cell survival and activation of the DNA damage response (DDR) through a decrease in the level of TRF2, a telomere-binding protein. These responses were correlated with reduced colony formation ability and accelerated telomere shortening in cancer cells upon the stable knockdown of REST. Interestingly, REST was down-regulated under oxidative stress conditions via ubiquitin proteasome system, suggesting that sustainability of REST expression is critical to determine cell survival during oxidative stress in a tumor microenvironment. Our results collectively indicate that REST-dependent TRF2 expression renders cancer cells resistant to DNA damage during oxidative stress, and mechanisms to overcome oxidative stress, such as high levels of REST or the stress-resistant REST mutants found in specific human cancers, may account for REST-dependent tumorigenesis.
authors: Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors: Jung-Hee
authors: JH
authors: Kwon
authors: Ji Hye
authors: JH
authors: Shin
authors: Eung-Sam
authors: ES
authors: Kim
authors: Namgyu
authors: N
authors: Lee
authors: Jin Young
authors: JY
authors: Park
authors: Bonik Samuel
authors: BS
authors: Koo
authors: Sun Mi
authors: SM
authors: Hong
authors: Chang Wook
authors: CW
authors: Park
authors: Kwan Yong
authors: KY
authors: Choi
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism; D059506:Telomere Shortening; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D035341:Telomeric Repeat Binding Protein 2; D044767:Ubiquitin-Protein Ligases; D000099229:RE1-Silencing Transcription Factor; C504753:TERF2 protein, human