CYBRD1 is transcriptionally regulated by RUNX1 and mediates JAK2/STAT3 signaling activation during ovarian cancer progression.

Abstract

Metastasis and chemoresistance are the leading causes of death in high-grade serous ovarian carcinoma (HGSOC). Our previous studies revealed that the membrane protein cytochrome b reductase 1 (CYBRD1) is a critical prognostic marker for HGSOC, but its role in HGSOC progression and molecular mechanisms remain unclear. Here, we reveal that CYBRD1 is a druggable factor that drives chemoresistance and tumor progression in HGSOC. Importantly, compared with that in their cisplatin-sensitive counterparts, CYBRD1 expression is elevated in cisplatin-resistant cells. Through genetic manipulation, we showed that CYBRD1 inhibition effectively re‑sensitizes cells to cisplatin and suppresses proliferation, migration, and invasion. Targeted gene expression profiling indicated that CYBRD1 inhibition markedly attenuated JAK2/STAT3 signaling. Using point mutants, we confirmed that phosphorylation of CYBRD1 at Tyr252 is essential for the interaction with JAK2, subsequent activation of JAK2/STAT3 signaling and mediating HGSOC progression. CYBRD1 inhibition significantly restored cisplatin sensitivity and exerted a synergistic tumoricidal effect. In vivo, combined CYBRD1 inhibition and cisplatin markedly reduced tumor metastasis. Furthermore, we found that RUNX1 regulates CYBRD1 transcription. These findings highlight that the combination of CYBRD1 inhibitors and conventional chemotherapy is a promising therapeutic strategy for HGSOC, especially in chemoresistant patients.