ZC3H13 Loss Drives Cancer Metastatic Progression by Disrupting m6A RNA Methylation

Aggressive metastatic cancer remains a major clinical challenge because of the unclear underlying mechanisms and the limited treatment options available. N6-Methyladenosine (m6A) is a reversible modification of RNA that is frequently altered in cancer, and inhibitors targeting regulators of this process have been shown to block tumorigenesis. A better understanding of the role of m6A modifications in driving metastatic properties could help reveal potential strategies to prevent and treat metastasis. In this study, we discovered loss of the m6A writer complex component ZC3H13 as a key regulator of metastatic progression. Co-loss of ZC3H13 together with RB1 and BRCA2 occurred in patients with metastatic prostate cancer. Functional in vitro and in vivo assays demonstrated that ZC3H13 loss changes m6A writer complex activity and target specificity, leading to decreased m6A methylation and increased stability of transcripts that promote migration and invasion. Treatment with FDA-approved m6A demethylase inhibitors effectively reduced the metastatic capabilities of ZC3H13-deficient cells. Together, these findings provide insights into how the m6A writer complex selectively methylates mRNAs, highlight the pathologic consequences of altered writer complex composition in cancer, and reveal therapeutic avenues for patients with metastatic cancer. SIGNIFICANCE: FDA-approved m6A demethylase inhibitors can inhibit metastasis driven by ZC3H13 deficiency, which reduces m6A methylation of select transcripts involved in migration and invasion, providing potential therapeutic options for patients with metastatic cancer.