组蛋白脱乙酰基酶5
组蛋白脱乙酰基酶
心理压抑
癌症研究
乙酰化
组蛋白
生物
抑制因子
组蛋白脱乙酰基酶2
转录因子
激酶
细胞生物学
遗传学
基因
基因表达
作者
Yingke Zhou,Xin Jin,Jian Ma,Duo Ding,Haojie Huang,Haoyue Sheng,Yuqian Yan,Yunqian Pan,Ting Wei,Liguo Wang,Heshui Wu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-01-08
卷期号:81 (6): 1486-1499
被引量:34
标识
DOI:10.1158/0008-5472.can-20-2828
摘要
Abstract The tumor-suppressor protein RB acts as a transcription repressor via interaction of its pocket domain with an LXCXE motif in histone deacetylase (HDAC) proteins such as HDAC1. Here, we demonstrate that HDAC5 deficient for the LXCXE motif interacts with both RB-N (via an FXXXV motif) and RB-C segments, and such interactions are diminished by phosphorylation of RB serine-249/threonine-252 and threonine-821. HDAC5 was frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increased histone H3 lysine 27 acetylation (H3K27-ac) and circumvented RB-mediated repression of cell-cycle–related pro-oncogenic genes. HDAC5 loss also conferred resistance to CDK4/6 inhibitors such as palbociclib in prostate and breast cancer cells in vitro and prostate tumors in vivo, but this effect was overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and define a new mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells. Significance: This study defines a previously uncharacterized role of HDAC5 in tumor suppression and provides a viable strategy to overcome CDK4/6 inhibitor resistance in HDAC5-deficent cancer.
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