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REST‐dependent expression of TRF2 renders non‐neuronal cancer cells resistant to DNA damage during oxidative stress
Author(s) -
Kwon JungHee,
Shin Ji Hye,
Kim EungSam,
Lee Namgyu,
Park Jin Young,
Koo Bonik Samuel,
Hong Sun Mi,
Park Chang Wook,
Choi Kwan Yong
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27741
Subject(s) - rest (music) , carcinogenesis , telomere , gene knockdown , gene silencing , biology , oxidative stress , dna damage , cancer , cancer research , cancer cell , microbiology and biotechnology , cell culture , gene , dna , genetics , endocrinology , medicine
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.