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
N1 - Funding Information:
Research reported in this publication was supported by the NCI of the NIH under grant numbers CA97098, CA166480, CA229716, and CA233084 awarded to D. Kufe and CA232979 awarded to S. Liu.
Publisher Copyright:
2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
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.
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U2 - 10.1158/0008-5472.CAN-19-1034
DO - 10.1158/0008-5472.CAN-19-1034
M3 - Article
C2 - 31519689
AN - SCOPUS:85075058845
SN - 0008-5472
VL - 79
SP - 5711
EP - 5722
JO - Cancer Research
JF - Cancer Research
IS - 22
ER -
