Loss of feedback regulation between FAM3B and androgen receptor driving prostate cancer progression.

Autor:	Ma T; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA., Jin L; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA., Bai S; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA., Liu Z; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA., Wang S; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Urological Department, Peking University Cancer Hospital & Institute, Beijing, China., Shen B; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei, China., Cho Y; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA., Cao S; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA., Sun MJS; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Fazli L; Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Zhang D; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; Duke University, Durham, NC, USA., Wedderburn C; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA., Zhang DY; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; University of Southern California, Los Angeles, CA, USA., Mugon G; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Ungerleider N; Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA., Baddoo M; Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA., Zhang K; Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, LA, USA., Schiavone LH; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Burkhardt BR; Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA., Fan J; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA., You Z; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA., Flemington EK; Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA., Dong X; Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Dong Y; Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.; Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA.
Jazyk:	angličtina
Zdroj:	Journal of the National Cancer Institute [J Natl Cancer Inst] 2024 Mar 07; Vol. 116 (3), pp. 421-433.
DOI:	10.1093/jnci/djad215
Abstrakt:	Background: Although the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression. Methods: We conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome. Results: This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling. Conclusion: Loss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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