The role of the ALKBH5 RNA demethylase in invasive breast cancer

Woodcock, Corinne L.; Alsaleem, Mansour; Toss, Michael S.; Lothion-Roy, Jennifer; Harris, Anna E.; Jeyapalan, Jennie N.; Blatt, Nataliya; Rizvanov, Albert A.; Miftakhova, Regina R.; Kariri, Yousif A.; Madhusudan, Srinivasan; Green, Andrew R.; Rutland, Catrin S.; Fray, Rupert G.; Rakha, Emad A.; Mongan, Nigel P.

Abstract

Background: N6-methyladenosine (m6A) is the most common internal RNA modification and is involved in regulation of RNA and protein expression. AlkB family member 5 (ALKBH5) is a m6A demethylase. Given the important role of m6A in biological mechanisms, m6A and its regulators, have been implicated in many disease processes, including cancer. However, the contribution of ALKBH5 to invasive breast cancer (BC) remains poorly understood. The aim of this study was to evaluate the clinicopathological value of ALKBH5 in BC. Methods: Publicly available data were used to investigate ALKBH5 mRNA alterations, prognostic significance, and association with clinical parameters at the genomic and transcriptomic level. Differentially expressed genes (DEGs) and enriched pathways with low or high ALKBH5 expression were investigated. Immunohistochemistry (IHC) was used to assess ALKBH5 protein expression in a large well-characterised BC series (n = 1327) to determine the clinical significance and association of ALKBH5 expression. Results: Reduced ALKBH5 mRNA expression was significantly associated with poor prognosis and unfavourable clinical parameters. ALKBH5 gene harboured few mutations and/or copy number alternations, but low ALKBH5 mRNA expression was seen. Patients with low ALKBH5 mRNA expression had a number of differentially expressed genes and enriched pathways, including the cytokine-cytokine receptor interaction pathway. Low ALKBH5 protein expression was significantly associated with unfavourable clinical parameters associated with tumour progression including larger tumour size and worse Nottingham Prognostic Index group. Conclusion: This study implicates ALKBH5 in BC and highlights the need for further functional studies to decipher the role of ALKBH5 and RNA m6A methylation in BC progression.

Citation

Woodcock, C. L., Alsaleem, M., Toss, M. S., Lothion-Roy, J., Harris, A. E., Jeyapalan, J. N., Blatt, N., Rizvanov, A. A., Miftakhova, R. R., Kariri, Y. A., Madhusudan, S., Green, A. R., Rutland, C. S., Fray, R. G., Rakha, E. A., & Mongan, N. P. (2024). The role of the ALKBH5 RNA demethylase in invasive breast cancer. Discover Oncology, 15(1), Article 343. https://doi.org/10.1007/s12672-024-01205-8

• Journal Article Type: Article
• Acceptance Date: Jul 30, 2024
• Online Publication Date: Aug 11, 2024
• Publication Date: Aug 11, 2024
• Deposit Date: Aug 29, 2024
• Publicly Available Date: Aug 29, 2024
• Journal: Discover Oncology
• Print ISSN: 2730-6011
• Electronic ISSN: 2730-6011
• Publisher: Springer
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 1
• Article Number: 343
• DOI: https://doi.org/10.1007/s12672-024-01205-8
• Keywords: N6-methyladenosine; Epitranscriptomics; m6A; Prognosis; Breast cancer
• Public URL: https://nottingham-repository.worktribe.com/output/38383365
• Publisher URL: https://link.springer.com/article/10.1007/s12672-024-01205-8
• Additional Information: Received: 17 January 2024; Accepted: 30 July 2024; First Online: 11 August 2024; : ; : This study was reviewed and approved by the Nottingham Research Ethics Committee, (approval # REC202313), and the research ethics committee of the University of Nottingham School of Veterinary Medicine and Science (approval # 2803 190814). The General Data Protection Regulation (GDPR) was applied, and informed consent obtained. The Helsinki Declaration of Human Rights was strictly observed.; : Not required.; : The authors have no conflicts of interest to declare.