MUC1-C integrates chromatin remodeling and PARP1 activity in the DNA damage response of triple-negative breast cancer cells

Masaaki Yamamoto, Caining Jin, Tsuyoshi Hata, Yota Yasumizu, Yan Zhang, Deli Hong, Takahiro Maeda, Masaaki Miyo, Masayuki Hiraki, Yozo Suzuki, Kunihiko Hinohara, Hasan Rajabi, Donald Kufe

研究成果: Article査読

5 被引用数 (Scopus)

抄録

The oncogenic MUC1-C protein is overexpressed in triple-negative breast cancer (TNBC) cells and contributes to their epigenetic reprogramming and chemoresistance. Here we show that targeting MUC1-C genetically or pharmacologically with the GO-203 inhibitor, which blocks MUC1-C nuclear localization, induced DNA double-strand breaks and potentiated cisplatin (CDDP)-induced DNA damage and death. MUC1-C regulated nuclear localization of the polycomb group proteins BMI1 and EZH2, which formed complexes with PARP1 during the DNA damage response. Targeting MUC1-C downregulated BMI1-induced H2A ubiquitylation, EZH2-driven H3K27 trimethylation, and activation of PARP1. As a result, treatment with GO-203 synergistically sensitized both mutant and wild-type BRCA1 TNBC cells to the PARP inhibitor olaparib. These findings uncover a role for MUC1-C in the regulation of PARP1 and identify a therapeutic strategy for enhancing the effectiveness of PARP inhibitors against TNBC.

本文言語English
ページ(範囲)2031-2041
ページ数11
ジャーナルCancer Research
79
8
DOI
出版ステータスPublished - 2019 4 15
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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