Epigenetically silenced KAT2B suppresses de novo lipogenesis through destroying HDAC5/LSD1 complex assembly in renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is a common Cancer that seriously threatens human health. Advanced RCC is characterized by poor responsiveness to radiotherapy and chemotherapy, with targeted therapy and immunotherapy currently serving as the primary treatment modalities. However, the issue of therapeutic resistance remains a major challenge, necessitating the identification of novel therapeutic targets. Emerging evidence indicates that dysregulated lipid metabolism is a hallmark of RCC and represents a potential therapeutic target for this disease.

Objectives: To elucidate the mechanisms underlying abnormal lipid metabolism in RCC and identify suitable targets for its treatment.

Methods: Bioinformatics screening and analysis were performed to identify hub gene. qRT-PCR, western blot, immunohistochemistry (IHC), and methylation-specific PCR (MSP) were employed to verify the target gene expression. CCK-8 assays, transwell assays, comprehensive targeted lipidomics, co-immunoprecipitation (Co-IP), and immunofluorescence were used to investigate biological functions and mechanisms. The in vivo functions, mechanisms, and translational potential of the target gene were further validated using 3D Cell Culture systems, Organoid models, and animal models.

Results: In this study, we identify Lysine Acetyltransferase 2B (KAT2B) as a lipid-related biomarker in RCC, demonstrating that its low expression is associated with poor patient prognosis. Promoter hypermethylation contributes to the reduced expression of KAT2B in RCC. Mechanistically, KAT2B acetylates HDAC5 at lysine 726 (K726), facilitating its interaction with Exportin1 and subsequent nuclear export. This process disrupts the nuclear HDAC5-LSD1 complex, enhances histone methylation, and suppresses the expression of fatty acid synthase (FASN). The loss of KAT2B leads to elevated FASN expression and lipid accumulation, driving RCC progression. Notably, pharmacological inhibition of FASN mitigates these effects.

Conclusion: Our findings reveal that KAT2B suppresses de novo lipogenesis by interfering with HDAC5-LSD1 complex assembly, and highlight the potential of FASN inhibitors as a therapeutic strategy for RCC patients with low KAT2B expression.

KAT2B; Lipogenesis; Renal cell carcinoma; TVB-2640.