The Proteasome Component PSMD14 Drives Myelomagenesis through a Histone Deubiquitinase Activity

The 19S regulatory particle (RP) of the proteasome is emerging as a promising target for the treatment of myeloma that are resistant to bortezomib, a selective inhibitor of the 20S core particle. However, the molecular basis underlying the targeting of the 19S RP for myeloma therapy remains to be elucidated. Here we report that, unexpectedly, the 19S RP component PSMD14 is physically associated with the myeloma driver, NSD2 on chromatin independent of 19S RP. We find that PSMD14 is a histone deubiquitinase acting on H2AK119, and that PSMD14-catalyzed H2AK119 deubiquitination facilitates NSD2-directed H3K36 di-methylation. Integrative genomic and epigenomic analyses reveal that the functional coordination between PSMD14 and NSD2 is associated with transcription activation of a cohort of genes including RELA that are critically involved in myelomagenesis. We show that RELA, in turn, transactivates PSMD14, establishing a positive feedback regulatory loop that explains well the long-reported clinical behaviours of myeloma. Chemical inhibition of PSMD14 sensitizes myeloma cells to bortezomib and confers a synergistic anti-myeloma activity with bortezomib, lenalidomide and dexamethasone. Importantly, the expression of PSMD14 is increasingly elevated as asymptomatic pre-malignant myeloma progresses to multiple myeloma, and its level of expression is inversely correlated with the overall survival and bortezomib-based therapeutic response of myeloma patients. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of this proteasome constituent as a therapeutic target to overcome the treatment limitation of myeloma.