Targeting superenhancer-driven PRKCN mediated mTOR-IRF4 signaling as a potential strategy against multiple myeloma

ABSTRACT: Multiple myeloma (MM) remains incurable, necessitating development of novel therapeutic targets. Deregulated PRKCN contributes to development of solid tumors, while its role in MM remains elusive. In present, we identified PRKCN as a superenhancer-driven gene abundantly expressed in MM. PRKCN was transactivated by NF-κB signaling intrinsically existing or exogenously provoked, nominating PRKCN as a novel NF-κB target gene. Constitutive or inducible knockdown of PRKCN significantly impaired cell growth and tumorigenicity, while overcoming drug resistance and triggering apoptosis. The growth-inhibition elicited by PRKCN depletion was considerably rescued by IRF4 overexpression, supporting PRKCN functioned through IRF4. Intriguingly, IRF4 reciprocally transactivated PRKCN, thereby forming a positive feedback loop. Furthermore, PRKCN favored IRF4 expression by activating mTORC1/C2 signaling, which was associated with direct and extensive interaction with mTOR. Unexpectedly, although PRKCN could directly phosphorylate mTOR in vitro, it modulated mTOR-IRF4 axis and MM cell growth independently of intrinsic kinase activity yet requiring phosphorylation of activation loop. Noteworthily, targeting PRKCN with an orally bioavailable inhibitor suppressed the growth of cell lines together with primary samples and overcame drug resistance in vitro, and also elicited robust efficacy in a cell line-derived xenograft and a patient-derived xenograft, which was connected with mitigated activation loop phosphorylation of PRKCN and mTOR-IRF4 axis. Collectively, our study delineates PRKCN function that links NF-κB signaling and mTOR-IRF4 axis orchestrating cell growth and survival, providing the proof-of-concept for potentially targeting PRKCN to antagonize MM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305283 | GEO | 2025/08/13

REPOSITORIES: GEO