N6-methyladenosine-modified DBT alleviates lipid accumulation and inhibits tumor progression in clear cell renal cell carcinoma through the ANXA2/YAP axis-regulated Hippo pathway

Cancer Communications

article

Daojia Miao¹  Qi Wang¹  Jian Shi¹  Qingyang Lv¹  Diaoyi Tan¹  Chuanyi Zhao¹  Zhiyong Xiong¹  Xiaoping Zhang¹ 

[1] Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology;Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

关键词: clear cell renal cell carcinoma;    lipid accumulation;    Hippo signaling;    N6-methyladenosine;    dihydrolipoamide branched chain transacylase E2;   

DOI  :  10.1002/cac2.12413

学科分类：社会科学、人文和艺术（综合）

来源: Springer

【 摘 要 】

Background The mechanism of metabolism reprogramming is an unsolved problem in clear cell renal cell carcinoma (ccRCC). Recently, it was discovered that the Hippo pathway altered tumor metabolism and promoted tumor progression. Thus, this study aimed at identifying key regulators of metabolism reprogramming and the Hippo pathway in ccRCC and pinpointing potential therapeutic targets for ccRCC patients.Methods Hippo-related gene sets and metabolic gene sets were used to screen potential regulators of the Hippo pathway in ccRCC. Public databases and samples from patients were applied to investigate the association of dihydrolipoamide branched chain transacylase E2 (DBT) with ccRCC and Hippo signaling. The role of DBT was confirmed by gain or loss of function assays in vitro and in vivo. Mechanistic results were yielded by luciferase reporter assay, immunoprecipitation, mass spectroscopy, and mutational studies.Results DBT was confirmed as a Hippo-related marker with significant prognostic predictive value, and its downregulation was caused by methyltransferase-like-3 (METTL3)-mediated N6-methyladenosine (m6A) modification in ccRCC. Functional studies specified DBT as a tumor suppressor for inhibiting tumor progression and correcting the lipid metabolism disorder in ccRCC. Mechanistic findings revealed that annexin A2 (ANXA2) interacted with the lipoyl-binding domain of DBT to activate Hippo signaling which led to decreased nuclear localization of yes1-associated transcriptional regulator (YAP) and transcriptional repression of lipogenic genes.Conclusions This study demonstrated a tumor-suppressive role for the DBT/ANXA2/YAP axis-regulated Hippo signaling and suggested DBT as a potential target for pharmaceutical intervention in ccRCC.

【 授权许可】

CC BY|CC BY-NC-ND