Prostate cancer (PCa) is one of the most common malignancies among men in industrialized countries and a leading cause of cancer-related mortality. While the five-year survival rate for localized early-stage PCa approaches almost 100%, it declines dramatically to 30–35% upon metastasis, with skeletal bone being the predominant metastatic site (observed in ~80% of cases) and no curative treatments currently available. The interplay between tumor cells and bone cells plays a pivotal role in the establishment and progression of bone metastases. Emerging evidence suggests that RNA-editing and modification processes enable cancer cells to adapt to new microenvironments, facilitating metastatic progression.

In this study, we investigated the effects of the bone microenvironment on the expression of almost 100 different RNA-modifying enzymes in PCa cells and validated them in two distinct patient-derived PCa cohorts. Next, we continued with functional studies of the most significant RNA regulators.

Our findings demonstrate that many RNA modifiers were deregulated in PCa cell lines in our in vitro model for the bone microenvironment compared to normal medium. In silico analyses of patient-derived PCa cohorts support these results, revealing significant upregulation of two key RNA modifiers, RBM15 and RBM15B, in bone metastases compared to primary tumors at both RNA and protein levels. These proteins are components of the m6A methyltransferase complex (MTC), which mediates N6-methyladenosine (m6A) RNA modifications—the most common RNA modification in all eukaryotes. Functional studies employing siRNA knockdown confirmed the essential role of the proteins in regulating m6A RNA methylation and significantly decreased cell growth of PCa cell lines.

In conclusion, these results identify m6A RNA methylation and its regulatory proteins; RBM15 and RBM15B as contributors to PCa progression. Furthermore, the in vitro screening results, as well as patient cohort analyses, suggest a role in bone metastasis and highlight their prognostic potential.