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

Research output: Contribution to journalArticle

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

Fingerprint

Triple Negative Breast Neoplasms
Chromatin Assembly and Disassembly
DNA Damage
Polycomb-Group Proteins
Double-Stranded DNA Breaks
Ubiquitination
Protein C
Epigenomics
Cisplatin
Down-Regulation
Poly(ADP-ribose) Polymerase Inhibitors
(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MUC1-C integrates chromatin remodeling and PARP1 activity in the DNA damage response of triple-negative breast cancer cells. / Yamamoto, Masaaki; Jin, Caining; Hata, Tsuyoshi; Yasumizu, Yota; Zhang, Yan; Hong, Deli; Maeda, Takahiro; Miyo, Masaaki; Hiraki, Masayuki; Suzuki, Yozo; Hinohara, Kunihiko; Rajabi, Hasan; Kufe, Donald.

In: Cancer Research, Vol. 79, No. 8, 15.04.2019, p. 2031-2041.

Research output: Contribution to journalArticle

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, vol. 79, no. 8, pp. 2031-2041. https://doi.org/10.1158/0008-5472.CAN-18-3259
Yamamoto, Masaaki ; Jin, Caining ; Hata, Tsuyoshi ; Yasumizu, Yota ; Zhang, Yan ; Hong, Deli ; Maeda, Takahiro ; Miyo, Masaaki ; Hiraki, Masayuki ; Suzuki, Yozo ; Hinohara, Kunihiko ; Rajabi, Hasan ; Kufe, Donald. / MUC1-C integrates chromatin remodeling and PARP1 activity in the DNA damage response of triple-negative breast cancer cells. In: Cancer Research. 2019 ; Vol. 79, No. 8. pp. 2031-2041.
@article{e57b9381407046d5b4a91ae94fbd9f67,
title = "MUC1-C integrates chromatin remodeling and PARP1 activity in the DNA damage response of triple-negative breast cancer cells",
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.",
author = "Masaaki Yamamoto and Caining Jin and Tsuyoshi Hata and Yota Yasumizu and Yan Zhang and Deli Hong and Takahiro Maeda and Masaaki Miyo and Masayuki Hiraki and Yozo Suzuki and Kunihiko Hinohara and Hasan Rajabi and Donald Kufe",
year = "2019",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-18-3259",
language = "English",
volume = "79",
pages = "2031--2041",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - MUC1-C integrates chromatin remodeling and PARP1 activity in the DNA damage response of triple-negative breast cancer cells

AU - Yamamoto, Masaaki

AU - Jin, Caining

AU - Hata, Tsuyoshi

AU - Yasumizu, Yota

AU - Zhang, Yan

AU - Hong, Deli

AU - Maeda, Takahiro

AU - Miyo, Masaaki

AU - Hiraki, Masayuki

AU - Suzuki, Yozo

AU - Hinohara, Kunihiko

AU - Rajabi, Hasan

AU - Kufe, Donald

PY - 2019/4/15

Y1 - 2019/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85064464909&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064464909&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-18-3259

DO - 10.1158/0008-5472.CAN-18-3259

M3 - Article

C2 - 30824588

AN - SCOPUS:85064464909

VL - 79

SP - 2031

EP - 2041

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 8

ER -