HIF2α promotes tumour growth in clear cell renal cell carcinoma by increasing the expression of NUDT1 to reduce oxidative stress

Abstract

BackgroundThe key role of hypoxia‐inducible factor 2alpha (HIF2α) in the process of renal cancer has been confirmed. In the field of tumour research, oxidative stress is also considered to be an important influencing factor. However, the relationship and biological benefits of oxidative stress and HIF2α in ccRCC remain unclear. This research attempts to explore the effect of oxidative stress on the cancer‐promoting effect of HIF2α in ccRCC and reveal its mechanism of action.MethodsThe bioinformatics analysis for ccRCC is based on whole transcriptome sequencing and TCGA database. The detection of the expression level of related molecules is realised by western blot and PCR. The expression of Nucleoside diphosphate‐linked moiety X‐type motif 1 (NUDT1) was knocked down by lentiviral infection technology. The functional role of NUDT1 were further investigated by CCK8 assays, transwell assays and cell oxidative stress indicator detection. The exploration of related molecular mechanisms is realised by Luciferase assays and Chromatin immunoprecipitation (ChIP) assays.ResultsMolecular screening based on knockdown HIF2α sequencing data and oxidative stress related data sets showed that NUDT1 is considered to be an important molecule for the interaction of HIF2α with oxidative stress. Subsequent experimental results showed that NUDT1 can cooperate with HIF2α to promote the progression of ccRCC. And this biological effect was found to be caused by the oxidative stress regulated by NUDT1. Mechanistically, HIF2α transcription activates the expression of NUDT1, thereby inhibiting oxidative stress and promoting the progression of ccRCC.ConclusionsThis research clarified a novel mechanism by which HIF2α stabilises sirtuin 3 (SIRT3) through direct transcriptional activation of NUDT1, thereby inhibiting oxidative stress to promote the development of ccRCC. It provided the possibility for the selection of new therapeutic targets for ccRCC and the study of combination medication regimens.

A Novel 7-Methylguanosine (m7G)-Related Gene Signature for Overall Survival Prediction in Patient with Clear Cell Renal Cell Carcinoma

“…Previous studies indicated that NUDT1 might provide diagnostic and prognostic value for KIRC [ 44 ]. A study revealed that NUDT1 is activated by HIF2 α transcription, thereby inhibiting oxidative stress and promoting the progression of ccRCC [ 45 ]. The roles of NUDT4 and NUDT10 remain ambiguous in ccRCC tumor progression and metastasis.…”

Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction

“…For instance, HIF-2α was associated with higher ferroptosis susceptibility in colorectal cancer cells, in murine colon tumors [51] and clear cell carcinoma cells [52] by regulation of cellular lipid and iron metabolism. However, HIF-2 signaling was also reported to reduce oxidative stress by inducing the transcription of nucleoside diphosphate-linked moiety X-type motif 1 in clear cell renal cell carcinoma, which promoted tumor growth [53]. HIF-1α, on the other hand, was attributed a protective effect against ferroptosis in several cancer cells by reducing iron and ROS levels [54], promoting lipid storage and regulating lipid metabolism [55][56][57].…”

FXR1 facilitates axitinib resistance in clear cell renal cell carcinoma via regulating KEAP1/Nrf2 signaling pathway

“…One typical feature of cancers is the capability to equilibrate the increased oxidative stress with high antioxidant levels [29]. As a transcription factor, Nrf2 is an essential stress response mediator, for which KEAP1 acts as a negative regulator [30].…”