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
N1 - Funding Information:
The C4-2B cell line was kindly provided by Dr. Li Jia, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant numbers CA97098, CA166480, CA229716 and CA233084 awarded to D.K. and CA232979 awarded to S.L.
Publisher Copyright:
© 2020, The Author(s).
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.
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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 -
