Renal cell carcinoma (RCC) remains a significant clinical challenge due to its increasing incidence and resistance to conventional therapy. This study identifies an unprecedented mechanism by which mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to RCC progression. From single-cell transcriptome, we observed a significant upregulation of MANF in RCC compared to its progenitor cells, the proximal tubular cells. Mechanistically, decreased N6-methyladenosine (m6A) modification on MANF mRNA, mediated by the upregulation of the m6A demethylase ALKBH5, led to reduced RNA degradation and increased MANF protein expression. Furthermore, while the common von Hippel-Lindau (VHL) deletion in RCC results in the accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, increased MANF efficiently mitigated ER stress by binding to phosphorylated inositol-requiring enzyme-1 alpha (IRE1α) and inhibited its phosphorylation, indicating that MANF-mediated ER stress resistance compensates for the negative effects of VHL depletion and contributes to the survival of RCC. Our findings highlight a potential therapeutic strategy for RCC by targeting the m6A-mediated regulation, directly degrading MANF protein or inhibiting its function.
Zixuan Liu,Yawen Wang,Yuxin Wang,Wenjing Dong,Xiaomin Xia,Erqun Song,Yang Song
Our previous studies illustrated tetrachlorobenzoquinone (TCBQ)-caused toxicities in neuron-like cells which imply its association with neurodegenerative disorders. Although it is known that TCBQ induces oxidative damage that in turn results in endoplasmic reticulum (ER) stress and apoptosis, it is unclear how TCBQ triggers the signaling switch from pro-survival (to restore cellular homeostasis) to pro-death (trigger apoptosis). Protein disulfide isomerase family proteins (PDIs) regulate the progress of various neurodegenerative disorders, including Parkinson’s disease and Alzheimer’s disease. We tested the hypothesis that subcellular translocation of PDIs implicates the survival/death signaling switch by inducing mitochondrial outer membrane permeabilization (MOMP). The rat pheochromocytoma PC12 cells were exposed to TCBQ, and the concentration-dependent ER stress was observed upon TCBQ treatment, as indicated by the increase in inositol-requiring kinase/endonuclease 1α (IRE1α) phosphorylation, C/EBP homologous protein (CHOP) expression, X-box-binding protein 1 (XBP1) splicing, and caspase 12 activation. Interestingly, pharmacological (or siRNA) abrogation of PDIA1/PDIA3 aggravated the loss of cell viability induced by the relatively low concentration (10 μM) of TCBQ. However, inhibition of PDIA1/PDIA3 rescued the high concentration (20 μM) of TCBQ-induced cell death. Further mechanistic study illustrated that PDIs initially acted to restore cellular homeostasis to pro-survival but that the constant ER stress promoted the signaling switch to pro-apoptotis by the release of PDIA1/PDIA3 from the ER lumen to induce Bak-dependent MOMP. Our findings suggested that subcellular translocation of PDIs determined the “life or death” fate of PC12 cells to TCBQ-induced oxidative insult.
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