m⁶A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer

Prostate cancer (PCa) is one of the most common cancers in men. Usually, most PCas at initial diagnosis are localized and hormone-dependent, and grow slowly. Patients with localized PCas have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive PCa is still dismal. N6-methyladenosine (m⁶A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m⁶A regulators. A few studies have shown that the abnormal expression of m⁶A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in PCa remain unclear. Here, we examined the expression profiles and methylation levels of 21 m⁶A regulators across the Cancer Genome Atlas (TCGA), 495 PCas by consensus clustering, and correlated the expression of m⁶A regulators with PCa progression and immune cell infiltration. Consensus clustering was applied for subtyping Pca samples into clusters based on the expression profiles of m⁶A regulators. Each subtype's signature genes were obtained by a pairwise differential expression analysis. Featured pathways of m⁶A subtypes were predicted by Gene Ontology. The m⁶A score was developed to predict m⁶A activation. The association of the m⁶A score with patients' survival, metastasis and immune cell infiltration was also investigated. We identified three distinct clusters in PCa based on the expression profiles of 21 m⁶A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m⁶A regulators involved in metabolic processes and immune responses in PCa. Moreover, we developed an m⁶A score to evaluate the m⁶A regulator activation for PCa. The m⁶A score is significantly associated with Gleason scores and metastasis in PCa. The predictive capacity of the m⁶A score on PCa metastasis was also validated in another independent cohort with an area under the curve of 89.5%. Hence, our study revealed the critical role of m⁶A regulators in PCa progression and the m⁶A score is a promising predictive biomarker for PCa metastasis.