Inhibition of SND1 overcomes chemoresistance in bladder cancer cells by promoting ferroptosis

Abstract

Chemotherapy remains one of the most important adjuvant treatments for bladder cancer (BC). However, similar to other malignancies, BC is prone to chemotherapy resistance and only approximately half of muscle-invasive patients with BC respond to chemotherapy. The present study aimed to reveal the mechanisms underlying chemoresistance in BC cells. Cell viabilities were assessed by CCK-8 assay. The differentiated expression of genes in chemoresistant and their parental BC cells were examined by RNA sequencing. Cell death was determined by flow cytometry. Different cell death inhibitors were used to determine the types of cell death. Levels of reactive oxygen species, iron, glutathione and malondialdehyde were assessed using the corresponding commercial kits. ChIP and dual luciferase activity assays were performed to investigate the interaction between staphylococcal nuclease and tumour domain containing 1 (SND1) and glutathione peroxidase 4 (GPX4) mRNA. RNAi was used to knockdown SND1 or GPX4. The results revealed that SND1 in BC cells were insensitive to cisplatin, and inhibition of SND1 overcame this resistance. Silencing of SND1 enhanced cell death induced by cisplatin by promoting ferroptosis in BC cells. Mechanistically, SND1 was revealed to bind to the 3'UTR region of GPX4 mRNA and stabilise it. Knockdown of GPX4 could also overcome chemoresistance, and overexpressing GPX4 reversed the effects of silencing of GPX4 on the chemosensitivity of BC cells. Thus, targeting the SND1-GPX4 axis may be a potential strategy to overcome chemoresistance in BC cells.

Unveiling the role of YARS1 in bladder cancer: A prognostic biomarker and therapeutic target

“…Recent investigations have shed light on the impact of the ferroptotic pathway on the prognosis and immunotherapy responses of individuals diagnosed with bladder cancer 30 . Additionally, the induction of ferroptosis has proven to be effective in overcoming the chemotherapy resistance exhibited by bladder cancer cells 31 . Moreover, induction of ferroptosis in various tumours inhibits tumour stemness 32–35 .…”

“… 30 Additionally, the induction of ferroptosis has proven to be effective in overcoming the chemotherapy resistance exhibited by bladder cancer cells. 31 Moreover, induction of ferroptosis in various tumours inhibits tumour stemness. 32 , 33 , 34 , 35 It has been discovered that many of the same molecular signalling networks regulate both cellular senescence and the maintenance of stem cell stemness.…”

Screening and identifying of biomarkers in early colorectal cancer and adenoma based on genome-wide methylation profiles

“…As an N6-methyladenosine (m6A) reader, SND1 is associated with methylation and can modify mRNA and regulate target mRNA stability [ 20 ]. SND1 expression was increased in tumors such as bladder cancer [ 21 ], glioma [ 22 ], and ovarian cancer [ 23 ] and correlated with proliferation and metastasis as well as chemoresistance. As previously reported, SND1 hypermethylation was found in CRC, which was consistent with our results of the present study [ 7 ].…”

Ferroptosis: An Emerging Target for Bladder Cancer Therapy

“…SND1 is considered a transcription factor that plays a role in various post-transcriptional regulatory activities [91]. Silencing SND1 and GPX4 might make cells sensitive to a chemotherapeutic like cisplatin, which would enhance ferroptosis in BC cells [92]. Excessive expression of GPX4 could counteract those effects.…”