The combination of BET and METTL3 inhibitors elicits synergistic antitumor effects in ovarian cancer cells via reducing SP1 and BCL-2 expression

Ovarian cancer (OC) remains a major health threat to woman despite treatment advances. New therapeutic strategies are demanded to persistently explored. In this study, we found that inhibitors of bromodomain and extra-Terminal domain (BET) and methyltransferase-like 3 (METTL3) exerted synergistic proliferative inhibition in different OC cell lines. In vitro synergism was translated into in vivo antitumor activity through the combination of BET inhibitor HJP-178 and METTL3 inhibitor STM2457. Mechanistically, this combination mainly enhanced apoptosis rather than affecting cell cycle arrest. Furthermore, it was revealed that HJP-178 decreased the transcription of Specificity protein 1 (SP1) while STM2457 lowered the N⁶-methyladenosine (m⁶A) levels of SP1 mRNA. Consequently, their combination synergistically reduces SP1 RNA and protein levels through both transcriptional and post-transcriptional modifications. Further exploration demonstrated that inhibiting SP1 directly downregulates the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), activating the caspase-mediated apoptotic pathway and triggering programmed cell death. Importantly, SP1 overexpression significantly reducing the apoptosis induction and proliferation inhibition induced by the combination. Similarly, BCL-2 overexpression mimicked the effects of increased SP1. These results demonstrate the critical roles of SP1 and BCL-2 in the synergistic antitumor activity between BET and METTL3 inhibitors. Collectively, our findings broaden the potential applications of both drug types and present a promising therapeutic approach for OC, warranting further investigation in clinical settings.