The NuRD complex-mediated p21 suppression facilitates chemoresistance in BRCA-proficient breast cancer

• Published in: Experimental cell research 2017-10, Vol.359 (2), p.458-465
• Main Authors: Hou, Ming-Feng, Luo, Chi-Wen, Chang, Tsung-Ming, Hung, Wen-Chun, Chen, Tzu-Yi, Tsai, Ya-Li, Chai, Chee-Yin, Pan, Mei-Ren
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Autoantigens - genetics; Autoantigens - metabolism; BRCAness; Cell Line, Tumor; CHD4; Chromatin Assembly and Disassembly; Cisplatin - pharmacology; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Databases, Protein; DNA - genetics; DNA - metabolism; DNA Breaks, Double-Stranded; DNA damage; DNA Repair; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic; HDAC1; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Humans; Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; p21; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Promoter Regions, Genetic; Protein Array Analysis; Signal Transduction
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2017.08.029

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. ~ 300bp 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. [Display omitted] •An epigenetic mechanism for p21WAF1 is proposed in breast cancer.•The mechanism relies on the CHD4-HDAC1 axis in controlling p21 transcripts.•CHD4 deficiency sensitizes cells to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibitor in reducing cell survival.•Targeting CHD4 should provide a strategy in the development of anti-cancer agents in BRCA-proficient breast cancer.