mRNA-Modified FUS/NRF2 Signalling Inhibits Ferroptosis and Promotes Prostate Cancer Growth

Abstract

Objective. Regarding the imperfect mechanism of occurrence and development of prostate adenocarcinoma (PRAD), this study investigated mRNA-modified FUS/NRF2 signalling to inhibit ferroptosis and promote prostate adenocarcinoma growth. Methods. Bioinformatics analysis was used to obtain the expression of FUS and its mRNA modification in PRAD. The expression of FUS in prostate cells (CRPC) and the level of m6A methylation modification, ferroptosis (P53 and GPX4), apoptosis (Caspase3), ferroptosis (P53 and GPX4), and apoptosis (Caspase3) in CRPC after ferroptosis inducer Erastin, ferroptosis inhibitor, and FUS knockdown were detected. Autophagy (LC3B), oxidative stress (GSH and ROS), and expression of NRF2/HO-1 pathway are indicators. Results. FUS was highly expressed in PRAD and phenomenally reduced the survival rate of patients. After knocking down FUS, the level of m6A methylation was significantly reduced, and the expressions of ferroptosis markers P53 and GPX4 were phenomenally reduced, while the levels of apoptosis and autophagy markers Caspase3 and LC3B remained unchanged. Upregulated and NRF2/HO-1 pathway indicators were upregulated. It shows that m6A methylation modification is reduced when FUS is the low expression, inhibits the expression of P53 and GPX4, downregulates GSH, upregulates ROS, activates the NRF2/HO-1 pathway, and promotes ferroptosis to inhibit the occurrence of RPAD. Conclusions. The increase of m6A methylation modification can increase the expression of FUS, thereby promoting the expression of P53 and GPX4, upregulating GSH, downregulating ROS, inhibiting the NRF2/HO-1 pathway, inhibiting ferroptosis, and promoting the growth of PRAD.

Exosomal HSPB1, interacting with FUS protein, suppresses hypoxia‐induced ferroptosis in pancreatic cancer by stabilizing Nrf2 mRNA and repressing P450

“…A previous study revealed that, as a famous RNA‐binding protein, FUS was able to bind to and stabilize the NRF2 mRNA. 16 Here, we verify the regulation of FUS protein on NRF2 expression in SW1990 cells. Our RNA‐IP results showed that FUS protein is directly bound to NRF2 mRNA (Figure 9A ).…”

Mechanism of ferroptosis in traditional chinese medicine for clinical treatment: A review

“…Nrf2 is also involved in activating different target genes of iron/GSH metabolism to prevent lipid peroxidation and ferroptosis ( Wang et al, 2016 ). Targeting Nrf2 or inhibiting cysteine/GSH metabolism causes uncontrolled oxidative stress and siderotoxicity, thereby arresting tumor growth and triggering iron-dependent cell death ( Wang et al, 2022 ).…”

Uncovering the Secrets of Prostate Cancer’s Radiotherapy Resistance: Advances in Mechanism Research

“…The overexpression of HECT and Copper Zinc Superoxide Dismutase Domain containing protein 1 (HACE1) in glioma tissues competes with Keap1 to prevent Nrf2 from being degraded via ubiquitination at the post-translational modification level and promotes the upregulation of Nrf2 transcriptional expression via the internal ribosome entry site (IRES) through La/SSB [ 76 ]. Targeting Nrf2 can induce ferroptosis in PCa cells [ 77 ], providing novel insight into the radiotherapy resistance of PCa. Therefore, Nrf2 is a critical target for improving treatment resistance in PCa [ 78 , 79 ].…”