Loss of feedback regulation between FAM3B and androgen receptor driving prostate cancer progression
© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissionsoup.com..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Journal of the National Cancer Institute - 116(2024), 3 vom: 07. März, Seite 421-433 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ma, Tianfang [VerfasserIn] |
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| Links: |
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| Themen: |
Cytokines |
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| Anmerkungen: |
Date Completed 08.03.2024 Date Revised 09.03.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/jnci/djad215 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM363402055 |
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| 100 | 1 | |a Ma, Tianfang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Loss of feedback regulation between FAM3B and androgen receptor driving prostate cancer progression |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 09.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissionsoup.com. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Receptors, Androgen |2 NLM | |
| 650 | 7 | |a Oncogene Proteins, Fusion |2 NLM | |
| 650 | 7 | |a Transcriptional Regulator ERG |2 NLM | |
| 650 | 7 | |a FAM3B protein, human |2 NLM | |
| 650 | 7 | |a Neoplasm Proteins |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 700 | 1 | |a Jin, Lianjin |e verfasserin |4 aut | |
| 700 | 1 | |a Bai, Shanshan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shuo |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Beibei |e verfasserin |4 aut | |
| 700 | 1 | |a Cho, Yeyoung |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Subing |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Meijuan J S |e verfasserin |4 aut | |
| 700 | 1 | |a Fazli, Ladan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, David |e verfasserin |4 aut | |
| 700 | 1 | |a Wedderburn, Chiyaro |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Derek Y |e verfasserin |4 aut | |
| 700 | 1 | |a Mugon, Gavisha |e verfasserin |4 aut | |
| 700 | 1 | |a Ungerleider, Nathan |e verfasserin |4 aut | |
| 700 | 1 | |a Baddoo, Melody |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Schiavone, Lovisa Holmberg |e verfasserin |4 aut | |
| 700 | 1 | |a Burkhardt, Brant R |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a You, Zongbing |e verfasserin |4 aut | |
| 700 | 1 | |a Flemington, Erik K |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Xuesen |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Yan |e verfasserin |4 aut | |
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