ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer.

Autor:	Bae SY; Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United States., Bergom HE; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, United States.; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United States., Day A; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, United States.; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United States.; Institute for Health Informatics, University of Minnesota, Minneapolis, MN, United States., Greene JT; Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United States., Sychev ZE; Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United States., Larson G; Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United States., Corey E; Department of Urology, University of Washington, Seattle, WA, United States., Plymate SR; Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, United States.; Geriatric Research, Education, and Clinical Center, Veterans Affairs (VA) Puget Sound Health Care System, Seattle, WA, United States., Freedman TS; Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United States.; Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, MN, United States.; Center for Immunology, University of Minnesota, Minneapolis, MN, United States., Hwang JH; Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, United States.; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United States.; Department of Urology, University of Washington, Seattle, WA, United States., Drake JM; Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United States.; Department of Urology, University of Washington, Seattle, WA, United States.; Department of Urology, University of Minnesota-Twin Cities, Minneapolis, MN, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in endocrinology [Front Endocrinol (Lausanne)] 2023 Mar 29; Vol. 14, pp. 1093332. Date of Electronic Publication: 2023 Mar 29 (Print Publication: 2023).
DOI:	10.3389/fendo.2023.1093332
Abstrakt:	Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer. NEPC is characterized by the loss of androgen receptor (AR) signaling and transdifferentiation toward small-cell neuroendocrine (SCN) phenotypes, which results in resistance to AR-targeted therapy. NEPC resembles other SCN carcinomas clinically, histologically and in gene expression. Here, we leveraged SCN phenotype scores of various cancer cell lines and gene depletion screens from the Cancer Dependency Map (DepMap) to identify vulnerabilities in NEPC. We discovered ZBTB7A, a transcription factor, as a candidate promoting the progression of NEPC. Cancer cells with high SCN phenotype scores showed a strong dependency on RET kinase activity with a high correlation between RET and ZBTB7A dependencies in these cells. Utilizing informatic modeling of whole transcriptome sequencing data from patient samples, we identified distinct gene networking patterns of ZBTB7A in NEPC versus prostate adenocarcinoma. Specifically, we observed a robust association of ZBTB7A with genes promoting cell cycle progression, including apoptosis regulating genes. Silencing ZBTB7A in a NEPC cell line confirmed the dependency on ZBTB7A for cell growth via suppression of the G1/S transition in the cell cycle and induction of apoptosis. Collectively, our results highlight the oncogenic function of ZBTB7A in NEPC and emphasize the value of ZBTB7A as a promising therapeutic strategy for targeting NEPC tumors. Competing Interests: EC is consultant of Dotquant and received research funding via institutional SRAs from AbbVie, Janssen Research, Gilead, Zenith Epigenetics, Bayer, GSK, Astra Zeneca, Kronos, Foghorn, MacroGenics, and Forma Pharmaceuticals. JMD has no conflicts relevant to this work. However, he holds equity in and serves as Chief Scientific Officer of Astrin Biosciences. This interest has been reviewed and managed by the University of Minnesota in accordance with its Conflict of Interest policies. None of these companies contributed to or directed any of the research reported in this article. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Bae, Bergom, Day, Greene, Sychev, Larson, Corey, Plymate, Freedman, Hwang and Drake.)
Databáze:	MEDLINE
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