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

Ming-Feng Hou1, Chi-Wen Luo2, Tsung-Ming Chang3

  • 1Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 804, Taiwan; Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Municipal Hsiao Kang Hospital, Kaohsiung, Taiwan.

Experimental Cell Research
|August 27, 2017
PubMed

Insights

CHD4 deficiency impairs cell survival by increasing p21 levels, impacting tumor suppressor genes. Targeting CHD4 offers a potential therapeutic strategy for BRCA-proficient breast cancer.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex is crucial for gene silencing.
  • CHD4, a core NuRD component, collaborates with histone deacetylase (HDAC) to suppress tumor suppressor genes (TSGs).

Purpose of the Study:

  • To elucidate the role of CHD4 in regulating the cyclin-dependent kinase inhibitor p21.
  • To investigate the therapeutic potential of targeting CHD4 in breast cancer treatment.

Main Methods:

  • Investigated CHD4's role in p21 regulation through promoter analysis.
  • Assessed the impact of CHD4 and p21 modulation on anti-cancer drug response (cisplatin, PARP inhibitors).
  • Utilized patient tissue analysis and bioinformatics to correlate CHD4 and p21 expression.

Main Results:

  • CHD4 deficiency disrupts HDAC1 recruitment to the p21 promoter, specifically within a ~300bp proximal region.
  • Knockdown of p21 rescues growth suppression in CHD4-depleted cells treated with cisplatin or PARP inhibitors.
  • A positive correlation between CHD4 and p21 expression was observed in patient tissues and bioinformatics analyses.

Conclusions:

  • CHD4 deficiency compromises cell survival by elevating p21 levels.
  • The CHD4-HDAC1-p21 axis is a key regulator of p21 transcription.
  • Targeting CHD4 presents a promising therapeutic avenue for BRCA-proficient breast cancer.
Keywords:
BRCAnessCHD4DNA damageHDAC1p21

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