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.

journal_name

Nat Commun

journal_title

Nature communications

authors

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

doi

10.1038/s41467-019-14219-6

subject

Has Abstract

pub_date

2020-01-17 00:00:00

pages

338

issue

1

issn

2041-1723

pii

10.1038/s41467-019-14219-6

journal_volume

11

pub_type

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