MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

Yota Yasumizu; Hasan Rajabi; Caining Jin; Tsuyoshi Hata; Sean Pitroda; Mark D. Long; Masayuki Hagiwara; Wei Li; Qiang Hu; Song Liu; Nami Yamashita; Atsushi Fushimi; Ling Kui; Mehmet Samur; Masaaki Yamamoto; Yan Zhang; Ning Zhang; Deli Hong; Takahiro Maeda; Takeo Kosaka; Kwok K. Wong; Mototsugu Oya; Donald Kufe

doi:10.1038/s41467-019-14219-6

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

Yota Yasumizu
, Hasan Rajabi
, Caining Jin
, Tsuyoshi Hata
, Sean Pitroda
, Mark D. Long
, Masayuki Hagiwara
, Wei Li
, Qiang Hu
, Song Liu
, Nami Yamashita
, Atsushi Fushimi
, Ling Kui
, Mehmet Samur
, Masaaki Yamamoto
, Yan Zhang
, Ning Zhang
, Deli Hong
, Takahiro Maeda
, Takeo Kosaka

Kwok K. Wong, Mototsugu Oya, Donald Kufe

Department of Biostatistics

Dana-Farber Cancer Institute
The University of Osaka
The University of Chicago
Roswell Park Cancer Institute
Keio University
New York University

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.

Original language	English
Article number	338
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-14219-6
State	Published - Dec 1 2020

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Yasumizu, Y., Rajabi, H., Jin, C., Hata, T., Pitroda, S., Long, M. D., Hagiwara, M., Li, W., Hu, Q., Liu, S., Yamashita, N., Fushimi, A., Kui, L., Samur, M., Yamamoto, M., Zhang, Y., Zhang, N., Hong, D., Maeda, T., ... Kufe, D. (2020). MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer. Nature Communications, 11(1), Article 338. https://doi.org/10.1038/s41467-019-14219-6

@article{c9d8a16e13fe4b5c9ac2fe58729dff55,

title = "MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer",

abstract = "Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.",

author = "Yota Yasumizu and Hasan Rajabi and Caining Jin and Tsuyoshi Hata and Sean Pitroda and Long, \{Mark D.\} and Masayuki Hagiwara and Wei Li and Qiang Hu and Song Liu and Nami Yamashita and Atsushi Fushimi and Ling Kui and Mehmet Samur and Masaaki Yamamoto and Yan Zhang and Ning Zhang and Deli Hong and Takahiro Maeda and Takeo Kosaka and Wong, \{Kwok K.\} and Mototsugu Oya and Donald Kufe",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-019-14219-6",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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Yasumizu, Y, Rajabi, H, Jin, C, Hata, T, Pitroda, S, Long, MD, Hagiwara, M, Li, W, Hu, Q, Liu, S, Yamashita, N, Fushimi, A, Kui, L, Samur, M, Yamamoto, M, Zhang, Y, Zhang, N, Hong, D, Maeda, T, Kosaka, T, Wong, KK, Oya, M & Kufe, D 2020, 'MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer', Nature Communications, vol. 11, no. 1, 338. https://doi.org/10.1038/s41467-019-14219-6

TY - JOUR

T1 - MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

AU - Yasumizu, Yota

AU - Rajabi, Hasan

AU - Jin, Caining

AU - Hata, Tsuyoshi

AU - Pitroda, Sean

AU - Long, Mark D.

AU - Hagiwara, Masayuki

AU - Li, Wei

AU - Hu, Qiang

AU - Liu, Song

AU - Yamashita, Nami

AU - Fushimi, Atsushi

AU - Kui, Ling

AU - Samur, Mehmet

AU - Yamamoto, Masaaki

AU - Zhang, Yan

AU - Zhang, Ning

AU - Hong, Deli

AU - Maeda, Takahiro

AU - Kosaka, Takeo

AU - Wong, Kwok K.

AU - Oya, Mototsugu

AU - Kufe, Donald

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.

AB - Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.

UR - https://www.scopus.com/pages/publications/85078010842

U2 - 10.1038/s41467-019-14219-6

DO - 10.1038/s41467-019-14219-6

M3 - Article

C2 - 31953400

AN - SCOPUS:85078010842

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 338

ER -

MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer

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