Cotter, Kellie A; Gallon, John; Uebersax, Nadine; Rubin, Philip; Meyer, Kate D; Piscuoglio, Salvatore; Jaffrey, Samie R; Rubin, Mark A (2021). Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance. Molecular cancer research, 19(8), pp. 1398-1411. American Association for Cancer Research AACR 10.1158/1541-7786.MCR-21-0014
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Recent evidence has highlighted the role of N 6-methyladenosine (m6A) in the regulation of mRNA expression, stability, and translation, supporting a potential role for posttranscriptional regulation mediated by m6A in cancer. Here, we explore prostate cancer as an exemplar and demonstrate that low levels of N 6-adenosine-methyltransferase (METTL3) is associated with advanced metastatic disease. To investigate this relationship, we generated the first prostate m6A maps, and further examined how METTL3 regulates expression at the level of transcription, translation, and protein. Significantly, transcripts encoding extracellular matrix proteins are consistently upregulated with METTL3 knockdown. We also examined the relationship between METTL3 and androgen signaling and discovered the upregulation of a hepatocyte nuclear factor-driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knockdown rendered the cells resistant to androgen receptor antagonists via an androgen receptor-independent mechanism driven by the upregulation of nuclear receptor NR5A2/LRH-1. IMPLICATIONS: These findings implicate changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) |
UniBE Contributor: |
Cotter, Kellie Anne, Rubin, Philip Daniel, Rubin, Mark Andrew |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1541-7786 |
Publisher: |
American Association for Cancer Research AACR |
Language: |
English |
Submitter: |
Marla Rittiner |
Date Deposited: |
24 Jan 2022 13:39 |
Last Modified: |
05 Dec 2022 16:00 |
Publisher DOI: |
10.1158/1541-7786.MCR-21-0014 |
PubMed ID: |
34088870 |
BORIS DOI: |
10.48350/163462 |
URI: |
https://boris.unibe.ch/id/eprint/163462 |
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