MIER2/PGC1A elicits sunitinib resistance via lipid metabolism in renal cell carcinoma

作者：Zhihao Wei, Yuzhong Ye, Chenchen Liu, Qi Wang, Yunxuan Zhang, Kailei Chen, Gong Cheng, Xiaoping Zhang · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.04.032 · 被引用次数：24 · 研究领域：Histone Deacetylase Inhibitors Research、Cancer, Lipids, and Metabolism、Ferroptosis and cancer prognosis

INTRODUCTION: Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system and accounts for more than 90 % of all renal tumors. Resistance to targeted therapy has emerged as a pivotal factor that contributes to the progressive deterioration of patients with advanced RCC. Metabolic reprogramming is a hallmark of tumorigenesis and progression, with an increasing body of evidence indicating that abnormal lipid metabolism plays a crucial role in the advancement of renal clear cell carcinoma. OBJECTIVES: Clarify the precise mechanisms underlying abnormal lipid metabolism and drug resistance. METHODS: Bioinformatics screening and analyses were performed to identify hub gene. qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assays, and other biological methods were used to explore and verify related pathways. Various cell line models and animal models were used to perform biological functional experiments. RESULTS: In this study, we identified Mesoderm induction early response 2 (MIER2) as a novel biomarker for RCC, demonstrating its role in promoting malignancy and sunitinib resistance by influencing lipid metabolism in RCC. Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. Furthermore, Trichostat...