MUC1-C activates the NuRD complex to drive dedifferentiation of triple-negative breast cancer cells

Tsuyoshi Hata, Hasan Rajabi, Hidekazu Takahashi, Yota Yasumizu, Wei Li, Caining Jin, Mark D. Long, Qiang Hu, Song Liu, Atsushi Fushimi, Nami Yamashita, Ling Kui, Deli Hong, Masaaki Yamamoto, Masaaki Miyo, Masayuki Hiraki, Takahiro Maeda, Yozo Suzuki, Mehmet K. Samur, Donald Kufe

Research output: Contribution to journalArticle

Abstract

The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic mucin 1 (MUC1) C-terminal subunit (MUC1-C) protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here, we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C!MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and posttranscriptionally induced CHD4 expression in basal- but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/ CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3, and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells. Significance: MUC1-C directly interacts with MYC to activate the NuRD complex, mediating regulation of the estrogen receptor in triple-negative breast cancer cells.

Original languageEnglish
Pages (from-to)5711-5722
Number of pages12
JournalCancer Research
Volume79
Issue number22
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Mi-2 Nucleosome Remodeling and Deacetylase Complex
Triple Negative Breast Neoplasms
Mucin-1
Chromatin Assembly and Disassembly
Protein Subunits
Acetylation
Epigenomics
Estrogen Receptors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MUC1-C activates the NuRD complex to drive dedifferentiation of triple-negative breast cancer cells. / Hata, Tsuyoshi; Rajabi, Hasan; Takahashi, Hidekazu; Yasumizu, Yota; Li, Wei; Jin, Caining; Long, Mark D.; Hu, Qiang; Liu, Song; Fushimi, Atsushi; Yamashita, Nami; Kui, Ling; Hong, Deli; Yamamoto, Masaaki; Miyo, Masaaki; Hiraki, Masayuki; Maeda, Takahiro; Suzuki, Yozo; Samur, Mehmet K.; Kufe, Donald.

In: Cancer Research, Vol. 79, No. 22, 01.01.2019, p. 5711-5722.

Research output: Contribution to journalArticle

Hata, T, Rajabi, H, Takahashi, H, Yasumizu, Y, Li, W, Jin, C, Long, MD, Hu, Q, Liu, S, Fushimi, A, Yamashita, N, Kui, L, Hong, D, Yamamoto, M, Miyo, M, Hiraki, M, Maeda, T, Suzuki, Y, Samur, MK & Kufe, D 2019, 'MUC1-C activates the NuRD complex to drive dedifferentiation of triple-negative breast cancer cells', Cancer Research, vol. 79, no. 22, pp. 5711-5722. https://doi.org/10.1158/0008-5472.CAN-19-1034
Hata, Tsuyoshi ; Rajabi, Hasan ; Takahashi, Hidekazu ; Yasumizu, Yota ; Li, Wei ; Jin, Caining ; Long, Mark D. ; Hu, Qiang ; Liu, Song ; Fushimi, Atsushi ; Yamashita, Nami ; Kui, Ling ; Hong, Deli ; Yamamoto, Masaaki ; Miyo, Masaaki ; Hiraki, Masayuki ; Maeda, Takahiro ; Suzuki, Yozo ; Samur, Mehmet K. ; Kufe, Donald. / MUC1-C activates the NuRD complex to drive dedifferentiation of triple-negative breast cancer cells. In: Cancer Research. 2019 ; Vol. 79, No. 22. pp. 5711-5722.
@article{fa7107cd01ec4d4784d54b8ce6aa9548,
title = "MUC1-C activates the NuRD complex to drive dedifferentiation of triple-negative breast cancer cells",
abstract = "The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic mucin 1 (MUC1) C-terminal subunit (MUC1-C) protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here, we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C!MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and posttranscriptionally induced CHD4 expression in basal- but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/ CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3, and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells. Significance: MUC1-C directly interacts with MYC to activate the NuRD complex, mediating regulation of the estrogen receptor in triple-negative breast cancer cells.",
author = "Tsuyoshi Hata and Hasan Rajabi and Hidekazu Takahashi and Yota Yasumizu and Wei Li and Caining Jin and Long, {Mark D.} and Qiang Hu and Song Liu and Atsushi Fushimi and Nami Yamashita and Ling Kui and Deli Hong and Masaaki Yamamoto and Masaaki Miyo and Masayuki Hiraki and Takahiro Maeda and Yozo Suzuki and Samur, {Mehmet K.} and Donald Kufe",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/0008-5472.CAN-19-1034",
language = "English",
volume = "79",
pages = "5711--5722",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "22",

}

TY - JOUR

T1 - MUC1-C activates the NuRD complex to drive dedifferentiation of triple-negative breast cancer cells

AU - Hata, Tsuyoshi

AU - Rajabi, Hasan

AU - Takahashi, Hidekazu

AU - Yasumizu, Yota

AU - Li, Wei

AU - Jin, Caining

AU - Long, Mark D.

AU - Hu, Qiang

AU - Liu, Song

AU - Fushimi, Atsushi

AU - Yamashita, Nami

AU - Kui, Ling

AU - Hong, Deli

AU - Yamamoto, Masaaki

AU - Miyo, Masaaki

AU - Hiraki, Masayuki

AU - Maeda, Takahiro

AU - Suzuki, Yozo

AU - Samur, Mehmet K.

AU - Kufe, Donald

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic mucin 1 (MUC1) C-terminal subunit (MUC1-C) protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here, we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C!MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and posttranscriptionally induced CHD4 expression in basal- but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/ CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3, and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells. Significance: MUC1-C directly interacts with MYC to activate the NuRD complex, mediating regulation of the estrogen receptor in triple-negative breast cancer cells.

AB - The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic mucin 1 (MUC1) C-terminal subunit (MUC1-C) protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here, we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C!MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and posttranscriptionally induced CHD4 expression in basal- but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/ CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3, and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells. Significance: MUC1-C directly interacts with MYC to activate the NuRD complex, mediating regulation of the estrogen receptor in triple-negative breast cancer cells.

UR - http://www.scopus.com/inward/record.url?scp=85075058845&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075058845&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-19-1034

DO - 10.1158/0008-5472.CAN-19-1034

M3 - Article

C2 - 31519689

AN - SCOPUS:85075058845

VL - 79

SP - 5711

EP - 5722

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 22

ER -