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

Abstract

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 (m 6 A) 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.

Comprehensive bioinformatics analysis reveals the role of cuproptosis-related gene Ube2d3 in myocardial infarction

“…According to relevant literature, Dbt can regulate the Hippo signaling pathway to affect the tumor growth of kidney renal clear cell carcinoma ( 16 ); DLAT has been identified as a key factor in the process of cuproptosis ( 11 ); Ube2D1 has been linked to the malignant progression of gastric cancer and breast cancer ( 17 , 18 ); Ube2d3 has been reported to promote p62 ubiquitination and aggravate impaired autophagic flow in myocardial ischemia-reperfusion injury ( 10 ). However, there has been no study investigating whether Ube2d3 can affect MI by inducing cuproptosis.…”

Comprehensive molecular analyses of cuproptosis-related genes with regard to prognosis, immune landscape, and response to immune checkpoint blockers in lung adenocarcinoma

“…However, the relationship between DBT and tumors is yet to be extensively studied. DBT has been characterized as a tumor suppressor that inhibits tumor progression and corrects lipid metabolism disorders through the DBT/ANXA2/ YAP axis-regulated Hippo signaling pathway in clear cell renal cell carcinoma (Miao et al 2023). DBT expression has also been recognized as an independent prognostic factor in kidney renal clear cell carcinoma, highly correlated with immunological checkpoints and targeted medications (Zhang et al 2023).…”

Exploring the Therapeutic Potential of β-Hydroxybutyrate (BHB) in Clear Cell Renal Cell Carcinoma: A Journey into Fat Browning, Autophagy, and Tumor Slimming

“…Tis aberrant lipid metabolism has been identifed as a crucial factor in the advancement of ccRCC and mirrors a prevalent trait in obesity characterized by excessive lipid production [2,28]. Consequently, substances capable of modulating this abnormal lipid metabolism in ccRCC may present promising prospects as potential therapies for this form of kidney cancer [29].…”