TRIM21 attenuates renal carcinoma lipogenesis and malignancy by regulating SREBF1 protein stability

Abstract

Background Metabolic reprogramming is a hallmark of various cancers. Targeting metabolic processes is a very attractive treatment for cancer. Renal cell carcinoma (RCC) is a type of metabolic disease, and the lipidomic profile of RCC is significantly altered compared with that of healthy tissue. However, the molecular mechanism underlying lipid metabolism regulation in RCC is not clear. Methods The XF long-chain fatty acid oxidative stress test kits were used to assess the dependence on long-chain fatty acids and mitochondrial function after knockdown TRIM21 in RCC cells. The effect of TRIM21 on the lipid content in RCC cells was determined by metabolomics analysis, Oil Red O staining, and cellular Nile red staining. qRT-PCR and western blot were used to explore the relationship between TRIM21 and lipogenesis, and then the key molecule sterol regulatory element binding transcription factor 1 (SREBF1) was identified to interact with TRIM21 by immunoprecipitation, which was also identified in an orthotopic model. Subsequently, the relevance and clinical significance of TRIM21 and SREBF1 were analyzed by The Cancer Genome Atlas (TCGA) database, and 239 tissues were collected from RCC patients. Results TRIM21 silencing attenuated the dependence of RCC cells on fatty acids, and enhanced lipid accumulation in RCC cells. TRIM21 overexpression significantly decreased lipid contents by decreasing the expression of lipogenic enzymes via ubiquitination-mediated degradation of SREBF1. SREBF1 is critical for TRIM21-mediated lipogenesis inhibition in vitro and in vivo. Moreover, TRIM21 expression is negatively correlated with SREBF1 expression, and TRIM21-SREBF1 is a reliable combinational biomarker for RCC prognosis. Conclusion The findings from this study reveal a novel pathway through which TRIM21 inhibits the lipid metabolism process of RCC and shed light on the development of targeted metabolic treatment and prognosis diagnosis of RCC.

PRMT1-mediated PGK1 arginine methylation promotes colorectal cancer glycolysis and tumorigenesis

“…Seahorse Bioscience Extracellular Flux Analyzer (XF96, Seahorse Bioscience Inc., North Billerica, MA, USA) was used to monitor glycolysis and mitochondrial function by measuring extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) as described in manufacturer’s instructions. Glucose uptake and lactate production were performed using the glucose assay kit (Shanghai Rongsheng Biotech, Shanghai, China) and lactate assay kit (Shanghai Rongsheng Biotech, Shanghai, China) following the manufacturer’s instructions as previously described [ 21 , 22 ], the detailed procedure was described in Supplementary Materials and Methods .…”

PRMT2 promotes RCC tumorigenesis and metastasis via enhancing WNT5A transcriptional expression

“…IHC assays were conducted following the standard streptavidin-peroxidase method, as previously reported [ 28 ]. The primary antibodies used were as follows: anti-PRMT2 1:100 dilution, anti-WNT5A 1:100 dilution, anti-Ki-67 1:100 dilution, and anti-Cyclin-D1 1:100 dilution.…”

“…Renal cancer tissue microarray (TMA) slides and corresponding patients’ clinicopathological information were obtained according to a previous report [ 28 ]. The detailed patient’s clinicopathological information was shown in Supplementary Information.…”

“…TMA immunohistochemistry and immunostaining were performed as previously described [ 28 ]. Detailed protocols were provided in the Supplementary Information.…”