MUC1-C Regulates Lineage Plasticity Driving Progression to Neuroendocrine Prostate Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jan 19

PMID 31953400

Citations 84

Authors

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

Affiliations

Soon will be listed here.

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.

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