NSUN5 Mediates Resistance to Doxorubicin via Up-regulation 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 in CRC remains unclear. This study revealed that NSUN5 was highly expressed in CRC through bioinformatics analysis and validation with local cohort. High expression of NSUN5 predicted poorer disease-free survival in CRC patients. Nsun5^-/- mice exhibited reduced tumor incidence and malignancy in the AOM/DSS-induced CRC model. Knockdown or knockout of NSUN5 resulted in diminished proliferation and migration in CRC cell lines, effects that were reversed by NSUN5 overexpression or reintroduction. Intriguingly, overexpression of NSUN5 conferred resistance to doxorubicin, an effective chemotherapeutic agent that leads to DNA damage, whereas NSUN5 deficiency increased CRC cells' sensitivity to doxorubicin, both in vitro and in vivo. Mechanistically, NSUN5 up-regulated the expression of BRCA2 and the BRCA1-interacting helicase 1 (BRIP1), and interacted with these proteins to prevent cell death in response to DNA damage. Analysis of the local cohort and public data sets showed positive correlations between NSUN5, BRCA2, and BRIP1 in CRC. These findings demonstrate the role of NSUN5 in CRC from the perspective of chemotherapy resistance, potentially offering innovative insights into clinical therapy and prognosis of CRC.