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Depletion of TRRAP Induces p53‐Independent Senescence in Liver Cancer by Down‐Regulating Mitotic Genes
Author(s) -
Kwan SuetYan,
Sheel Ankur,
Song ChunQing,
Zhang XiaoOu,
Jiang Tingting,
Dang Hien,
Cao Yueying,
Ozata Deniz M.,
Mou Haiwei,
Yin Hao,
Weng Zhiping,
Wang Xin Wei,
Xue Wen
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30807
Subject(s) - biology , cancer research , cell growth , mitosis , cell cycle , telomerase , gene knockdown , cancer , genetics , cell culture , gene
Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments, and the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Using a kinome CRISPR screen in three human HCC cell lines, we identified transformation/transcription domain‐associated protein ( TRRAP ) as an essential gene for HCC cell proliferation. TRRAP has been implicated in oncogenic transformation, but how it functions in cancer cell proliferation is not established. Here, we show that depletion of TRRAP or its co‐factor, histone acetyltransferase KAT5, inhibits HCC cell growth through induction of p53‐independent and p21‐independent senescence. Integrated cancer genomics analyses using patient data and RNA sequencing identified mitotic genes as key TRRAP/KAT5 targets in HCC, and subsequent cell cycle analyses revealed that TRRAP‐depleted and KAT5‐depleted cells are arrested at the G2/M phase. Depletion of topoisomerase II alpha ( TOP2A ), a mitotic gene and TRRAP/KAT5 target, was sufficient to recapitulate the senescent phenotype of TRRAP/KAT5 knockdown. Conclusion: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation by activating mitotic genes. Targeting the TRRAP/KAT5 complex is a potential therapeutic strategy for HCC.