NSUN5 Mediates Resistance to Doxorubicin via Upregulation of DNA Damage Repair Proteins BRCA2 and BRIP1 in Colorectal Cancer

Despite advancements in diagnosis and therapy, chemotherapy resistance and metastasis remain significant challenges for colorectal cancer (CRC) patients. Addressing resistance to cell death is crucial for improving cancer treatment outcomes. NOP2/Sun RNA methyltransferase 5 (NSUN5) has been implicated in cancers, but its role in chemotherapy resistance of CRC remains unclear. Herein we reveal that NSUN5 is highly expressed in CRC through bioinformatics analysis and validation using human and mice CRC tissues. High expression of NSUN5 predicted poorer disease-free survival in CRC patients. Nsun5-deficient mice exhibited reduced tumor incidence and malignancy in an AOM/DSS-induced CRC model. NSUN5 knockdown or knockout showed diminished proliferation and migration in CRC cell lines, which was reversed by NSUN5 overexpression or reintroduction. Intriguingly, overexpression of NSUN5 conferred resistance to doxorubicin, an effective chemotherapeutic agent leads to DNA damage, whereas NSUN5 deficiency increased CRC cells' sensitivity to the drug, both in vitro and in vivo. Mechanistically, NSUN5 upregulated BRCA2 and BRCA1-interacting helicase 1 (BRIP1) expression and interacted with these proteins to prevent cell death in response to DNA damage. Analysis of our local cohort and public data sets showed a positive correlation between NSUN5, BRCA2, and BRIP1 in CRC patients. Collectively, we uncover the role of NSUN5 in CRC progression from the perspective of chemotherapy resistance, potentially offering innovative insight on the clinical therapy and prognosis of CRC.