circUBR5 promotes ribosome biogenesis and induces docetaxel resistance in triple-negative breast cancer cell lines via the miR-340-5p/CMTM6/c-MYC axis.

OBJECTIVE

Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways.

METHODS

DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated.

RESULTS

CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6.

CONCLUSION

circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance.