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 KosakaKwok K. Wong, Mototsugu Oya, Donald Kufe

研究成果: Article査読

63 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号338
ジャーナルNature communications
11
1
DOI
出版ステータスPublished - 2020 12月 1

ASJC Scopus subject areas

  • 化学 (全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 物理学および天文学(全般)

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