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

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Abstract

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.

Original languageEnglish
Pages (from-to)2031-2041
Number of pages11
JournalCancer Research
Volume79
Issue number8
DOIs
Publication statusPublished - 2019 Apr 15
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yamamoto, M., Jin, C., Hata, T., Yasumizu, Y., Zhang, Y., Hong, D., Maeda, T., Miyo, M., Hiraki, M., Suzuki, Y., Hinohara, K., Rajabi, H., & Kufe, D. (2019). MUC1-C integrates chromatin remodeling and PARP1 activity in the DNA damage response of triple-negative breast cancer cells. Cancer Research, 79(8), 2031-2041. https://doi.org/10.1158/0008-5472.CAN-18-3259