Y10 phosphorylation of LDHA promotes the release of extracellular vesicle-derived circSEPT9 to enhance the chemoresistance of triple negative breast cancer cells via modulation of the miR-515-5p/KIAA1429 axis.

OBJECTIVE

Extracellular vesicle (EV)-derived RNAs play crucial roles in cancer biology and therapeutic resistance. This study investigated how EV-derived circSEPT9 mediates doxorubicin (DOX) resistance in triple negative breast cancer (TNBC).

METHODS

TNBC tissues and samples were analyzed alongside MDA-MB-231 and MDA-MB-231/ADR cells. The molecular interplay among circSEPT9, KIAA1429, and miR-515-5p was explored to elucidate the regulatory axis underlying drug resistance. EVs were purified to assess the clinical diagnostic potential of EV-circSEPT9. Functional assays employing lactate dehydrogenase A (LDHA) knockdown and rescue with Flag-tagged human LDHA WT or Y10F mutant constructs were conducted to examine the significance of LDHA Y10 phosphorylation in EV-circSEPT9 release and DOX resistance.

RESULTS

circSEPT9 silencing impaired proliferation, invasion, and colony formation of DOX-resistant TNBC cells while increasing their sensitivity to DOX through suppression of KIAA1429-mediated m6A modification. EVs from resistant cells transferred circSEPT9 to sensitive cells, thereby enhancing their drug resistance and tumor growth capacity. LDHA Y10 phosphorylation was found to be indispensable for EV-circSEPT9 secretion and the subsequent intercellular transfer of DOX resistance.

CONCLUSION

Phosphorylated LDHA (Y10) promotes EV-circSEPT9 secretion, elevating intracellular circSEPT9 levels in recipient TNBC cells. By functioning as a competing endogenous RNA (ceRNA) that sponges miR-515-5p, circSEPT9 upregulates KIAA1429, augments m6A methylation, and drives the development of chemoresistance.