Abstract 4037: Epigenetically-controlled CEBPB regulates kidney cancer tumorigenesis via GPD1L-mediated ether lipid synthesis

Abstract The VHL-HIF axis has been recognized as a major regulator of lipid accumulation and tumorigenesis in clear cell renal cell carcinoma (ccRCC), but a growing number of VHL-HIF-independent pathways suggests possible alternative regulators. By screening epigenetic drivers and transcription factors, we identified CCAAT/enhancer-binding protein beta (CEBPB) as a key VHL-independent transcription factor crucial to lipid-related ccRCC progression, which was confirmed through in vitro/vivo experiments. CEBPB levels, regulated by H3K27ac and H3K4me, were also correlated with various poor prognostic factors in ccRCC patients. Mechanistically, CEBPB transcriptionally repressed glycerol-3-phosphate dehydrogenase 1-like (GPD1L), causing substrate (dihydroxyacetonephophate) accumulation for ether lipid synthesis. This enhanced Akt activation through membrane recruitment, and the subsequent downregulation of carnitine palmitoyltransferase 1A (CPT1A) led to lipid accumulation. Connecting multiple elements of the Hallmarks of Cancer in an unbranched path, the CEBPB-GPD1L-ether lipid-Akt-CPT1A axis is proposed as a new VHL-independent mechanism of lipid-related ccRCC tumorigenesis. Significance: The identification of CEBPB as a VHL-independent regulator of lipid metabolism and tumorigenesis shows how major cancer hallmarks (epigenetics, metabolites, and signaling) can be orchestrated by single factor. The proposed CEBPB-GPD1L-ether lipid-Akt-CPT1A axis provides new insights and therapeutic potentials for the regulation of lipid-related tumorigenesis in ccRCC Citation Format: Thi Ha Nguyen, Xuan Linh Mai, Tin Tin Manh Nguyen, Hoonsik Nam, Sunghyouk Park, Ji Yun Lee. Epigenetically-controlled CEBPB regulates kidney cancer tumorigenesis via GPD1L-mediated ether lipid synthesis [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 4037.