Abstract 1183: Non-canonical RNA binding of the MYBL2 transcription factor promotes melanoma

Abstract Melanoma originates from melanocytes, and malignant transformation of melanocytes is affected by various factors, including non-mutational gene alterations. MYBL2 is a transcription factor primarily known for its role in regulating cell cycle progression, and in this study, we showed that MYBL2 copy number gains occur in one fifth of melanoma patients. We demonstrated that aberrant MYBL2 upregulation promotes melanoma growth in vitro and in vivo while its silencing has the opposite effects. Interestingly, a MYBL2 transactivation-deficient mutant retains oncogenic function, indicating that MYBL2 promotes melanoma growth independent of its transcription factor function. Notably, we found that MYBL2 is a non-canonical RNA binding protein, and its RNA binding is crucial for its melanoma-promoting function. MYBL2 binds RNA through an arginine rich motif and a C-terminal RNA binding domain, crosslinking-immunoprecipitation followed by high-throughput sequencing revealed that MYBL2 primarily binds introns of protein-coding genes in the nucleus. Moreover, MYBL2 does not affect the fate and function of its direct mRNA targets. Instead, binding to RNA enhances the association of MYBL2 with chromatin, thereby indirectly rewiring a transcriptional program that correlates with poor patient survival. Surprisingly, we observed that MYBL2 binds RNA exclusively in melanoma cells, but not in melanocytes. This phenomenon is primarily due to the mRNA expression landscape found in melanoma cells, and modifications of MYBL2 protein may also be involved to a lesser extent. In summary, our work identified a novel oncogenic function of MYBL2 through its RNA binding activity, extending our current understanding of MYBL2 and highlighting a critical mechanism in melanoma progression. Citation Format: Kaizhen Wang, Xiaonan Xu, Shiun Chang, Olga Vera, Nhan Phan, Xiaoqing Yu, Florian A. Karreth. Non-canonical RNA binding of the MYBL2 transcription factor promotes melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1183.