ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer
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 resemble...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1093332/full |
| _version_ | 1797857814416195584 |
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| author | Song Yi Bae Hannah E. Bergom Hannah E. Bergom Abderrahman Day Abderrahman Day Abderrahman Day Joseph T. Greene Zoi E. Sychev Gabrianne Larson Eva Corey Stephen R. Plymate Stephen R. Plymate Tanya S. Freedman Tanya S. Freedman Tanya S. Freedman Justin H. Hwang Justin H. Hwang Justin H. Hwang Justin M. Drake Justin M. Drake Justin M. Drake |
| author_facet | Song Yi Bae Hannah E. Bergom Hannah E. Bergom Abderrahman Day Abderrahman Day Abderrahman Day Joseph T. Greene Zoi E. Sychev Gabrianne Larson Eva Corey Stephen R. Plymate Stephen R. Plymate Tanya S. Freedman Tanya S. Freedman Tanya S. Freedman Justin H. Hwang Justin H. Hwang Justin H. Hwang Justin M. Drake Justin M. Drake Justin M. Drake |
| author_sort | Song Yi Bae |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T21:03:53Z |
| format | Article |
| id | doaj.art-3e48ddb167a545a593cf9fd00b156061 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-09T21:03:53Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-3e48ddb167a545a593cf9fd00b1560612023-03-29T05:18:19ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-03-011410.3389/fendo.2023.10933321093332ZBTB7A as a novel vulnerability in neuroendocrine prostate cancerSong Yi Bae0Hannah E. Bergom1Hannah E. Bergom2Abderrahman Day3Abderrahman Day4Abderrahman Day5Joseph T. Greene6Zoi E. Sychev7Gabrianne Larson8Eva Corey9Stephen R. Plymate10Stephen R. Plymate11Tanya S. Freedman12Tanya S. Freedman13Tanya S. Freedman14Justin H. Hwang15Justin H. Hwang16Justin H. Hwang17Justin M. Drake18Justin M. Drake19Justin M. Drake20Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesDepartment of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesDivision of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United StatesDepartment of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesDivision of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United StatesInstitute for Health Informatics, University of Minnesota, Minneapolis, MN, United StatesDepartment of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesDepartment of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesDepartment of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesDepartment of Urology, University of Washington, Seattle, WA, United StatesDepartment of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, United StatesGeriatric Research, Education, and Clinical Center, Veterans Affairs (VA) Puget Sound Health Care System, Seattle, WA, United StatesDepartment of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesMasonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesCenter for Immunology, University of Minnesota, Minneapolis, MN, United StatesDepartment of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesDivision of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United StatesDepartment of Urology, University of Washington, Seattle, WA, United StatesDepartment of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesDepartment of Urology, University of Washington, Seattle, WA, United States0Department of Urology, University of Minnesota-Twin Cities, Minneapolis, MN, United StatesNeuroendocrine 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.https://www.frontiersin.org/articles/10.3389/fendo.2023.1093332/fullZBTB7Aneuroendocrine prostate cancer (NEPC)castration-resistant prostate cancer (CRPC)small-cell neuroendocrine (SCN)cancer dependency map (DepMap)RET receptor tyrosine kinase |
| spellingShingle | Song Yi Bae Hannah E. Bergom Hannah E. Bergom Abderrahman Day Abderrahman Day Abderrahman Day Joseph T. Greene Zoi E. Sychev Gabrianne Larson Eva Corey Stephen R. Plymate Stephen R. Plymate Tanya S. Freedman Tanya S. Freedman Tanya S. Freedman Justin H. Hwang Justin H. Hwang Justin H. Hwang Justin M. Drake Justin M. Drake Justin M. Drake ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer Frontiers in Endocrinology ZBTB7A neuroendocrine prostate cancer (NEPC) castration-resistant prostate cancer (CRPC) small-cell neuroendocrine (SCN) cancer dependency map (DepMap) RET receptor tyrosine kinase |
| title | ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer |
| title_full | ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer |
| title_fullStr | ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer |
| title_full_unstemmed | ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer |
| title_short | ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer |
| title_sort | zbtb7a as a novel vulnerability in neuroendocrine prostate cancer |
| topic | ZBTB7A neuroendocrine prostate cancer (NEPC) castration-resistant prostate cancer (CRPC) small-cell neuroendocrine (SCN) cancer dependency map (DepMap) RET receptor tyrosine kinase |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1093332/full |
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