MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis

Abstract

Background Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation. Methods We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay. Results This study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM. Conclusion Our findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.

Identification of a novel lactylation-related gene signature predicts the prognosis of multiple myeloma and experiment verification

“…In MM, there has been numerous studies on the role of lactate in malignant cell proliferation and drug resistance, and lactate promotes protein lactylation, which is a key factor in promoting resistance 13 , 14 . A study has shown that exogenously increased lactate promotes insulin like growth factor receptor-1 (IGF-1R) lactylation, while repressing IGF-1R lactylation inhibits MET proto-oncogene, receptor tyrosine kinase (MET) activation and weakens the proteasome inhibitors resistance of MM cells 15 . These mechanisms suggest that targeting lactylation and related pathways, may be a potential strategy for treating MM.…”

The relationship and clinical significance of lactylation modification in digestive system tumors

“…Lactylation has also been linked to proteasome inhibitor resistance. MUC20 inhibits the lactylation of MET, thereby reducing tumor cell resistance to proteasome inhibitors, indicating a role for lactylation in the development of drug resistance in tumor cells [ 24 ]. Furthermore, lactylation enhances SLUG expression by inhibiting PTEN transcriptional activity, which subsequently suppresses autophagy and affects cell function and tissue repair [ 25 ].…”