The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer

Haigh, Daisy B.; Woodcock, Corinne L.; Lothion-Roy, Jennifer; Harris, Anna E.; Metzler, Veronika M.; Persson, Jenny L.; Robinson, Brian D.; Khani, Francesca; Alsaleem, Mansour; Ntekim, Atara; Madhusudan, Srinivasan; Davis, Melissa B.; Laursen, Kristian B.; Gudas, Lorraine J.; Rutland, Catrin S.; Toss, Michael S.; Archer, Nathan; Bodi, Zsuzsanna; Rakha, Emad A.; Fray, Rupert G.; Jeyapalan, Jennie N.; Mongan, Nigel P.

Abstract

Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa.

Citation

Haigh, D. B., Woodcock, C. L., Lothion-Roy, J., Harris, A. E., Metzler, V. M., Persson, J. L., …Mongan, N. P. (2022). The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer. Cancers, 14(20), Article 5148. https://doi.org/10.3390/cancers14205148

• Journal Article Type: Article
• Acceptance Date: Oct 18, 2022
• Online Publication Date: Oct 20, 2022
• Publication Date: Oct 1, 2022
• Deposit Date: Oct 21, 2022
• Publicly Available Date: Oct 24, 2022
• Journal: Cancers
• Electronic ISSN: 2072-6694
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 20
• Article Number: 5148
• DOI: https://doi.org/10.3390/cancers14205148
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/12621988
• Publisher URL: https://www.mdpi.com/2072-6694/14/20/5148