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

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2025-01, Vol.59, p.101062, Article 101062
• Main Authors: Wang, Xuedong, Wang, Xinping, Gu, Juan, Wei, Yilei, Wang, Yueping
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; c-MYC; Cell Line, Tumor; circUBR5; CMTM6; Docetaxel - pharmacology; Docetaxel resistance; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; MARVEL Domain-Containing Proteins - genetics; MARVEL Domain-Containing Proteins - metabolism; MicroRNAs - genetics; miR-340-5p; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Ribosomes - genetics; Ribosomes - metabolism; Signal Transduction; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triple-negative breast cancer
• ISSN: 1476-5586; 1476-5586
• DOI: 10.1016/j.neo.2024.101062

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. 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. 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. 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.