LAUSR

The small MAF family of transcription factors, consisting of MAFG, MAFF, and MAFK, dimerize with CNC/BACH proteins to regulate diverse transcriptional programs. Previously, we have shown that miRNA-29 suppresses melanoma development, at least in part, by repressing MAFG expression. Moreover, analysis of the TCGA revealed frequent copy number gains and/or overexpression of MAFG in melanoma. However, whether MAFG has oncogenic effects in and is critical for melanoma is unknown. We found that silencing of MAFG, but not MAFF or MAFK, abrogates growth of melanoma cells in vitro, while melanocyte cell lines are less reliant on MAFG. Conversely, MAFG overexpression promoted proliferation and focus formation of human melanocyte and melanoma cell lines. Using a high-throughput melanoma mouse modeling (ESC-GEMM) platform, we found that in vivo overexpression of MAFG in BRAFV600E; PTEN+/- mice potently accelerated melanoma development. RNA-sequencing revealed that MAFG regulates transcriptional programs associated with hypoxic and immune responses. Accordingly, MAFG overexpressing cells exhibited better ability to survive under hypoxic conditions, probably through the regulation of HIF1A. Moreover, MAFG overexpressing cells showed increased expression of cytokines of the of the C-C chemokine family, CCL3 and CCL5. MAFG overexpressing tumors from ESC-GEMM mice and MAFG-High melanomas from TCGA had features of immune-cold milieus, characterized by reduced infiltration of CD45+ immune cells and CD8+ T cells. Altogether, we demonstrate that MAFG promotes melanomagenesis, in part, by regulating the response to hypoxic conditions and chemokine expression, which may rewire the tumor immune microenvironment. Citation Format: Olga Vera, Michael Martinez, Florian A. Karreth. MAFG promotes melanomagenesis through the transcriptional regulation of hypoxic and immune responses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3739.