Journal
EXPERIMENTAL CELL RESEARCH
Volume 359, Issue 2, Pages 458-465Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2017.08.029
Keywords
CHD4; p21; HDAC1; BRCAness; DNA damage
Categories
Funding
- Ministry of Science and Technology of Republic of China [105-2314-B-037-001, 105-2314-B-037-038-MY3]
- Research Center for Environmental Medicine, Kaohsiung Medical University [KMU-TP104Al2, KMU-TP105A15]
- Kaohsiung Medical University Hospital [KMUH], Kaohsiung, Taiwan [105-5R27]
- Taiwan Ministry of Health and Welfare [MOHW106-TDU-B-212-144007]
- Health and Welfare surcharge of tobacco products
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The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex play a role in silencing gene expression. CHD4, the core component of the NuRD complex, which cooperates with histone deacetylase in reducing tumor suppressor genes (TSGs). To dissect the mechanisms underlying cancer promotion, we clarify the role of CHD4 in cyclin-dependent kinase inhibitor protein p21. Here, our data indicates that CHD4 deficiency impairs the recruitments of HDAC1 to the p21 promoter similar to 300 bp proximal promoter region is responsible for CHD4-HDAC1 axis-mediated p21 transcriptional activity. For identifying the role of anti-cancer drug response, knockdown of p21 overcomes cisplatin and poly-(ADP-ribose) polymerase (PARP) inhibitor-mediated growth suppression in CHD4-depleted cells. Consistent with in vitro data, tissue of patients and bioinformatics approach also showed positive correlation between CHD4 and p21. Overall, our findings not only identify that CHD4 deficiency preferentially impairs cell survival via increasing the level of p21, but also establishes targeting CHD4 as a potential therapeutic implication in BRCA-proficient breast cancer treatment.
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