Noncanonical role of KDM5C in conferring bortezomib resistance via the PERK‒Nrf2 axis in multiple myeloma

Conventionally, KDM5C functions as a specific demethylase that targets histone H3 lysine 4 dimethyl and trimethyl modifications, crucial for gene expression. However, the role of KDM5C in multiple myeloma (MM) progression and bortezomib (BTZ) resistance has remained elusive. In this study, we found noncanonical functions of KDM5C in MM. Specifically, KDM5C binds to CBP and MYC, conferring BTZ resistance in MM through a demethylase-independent mechanism. Our investigations revealed that KDM5C is markedly upregulated in BTZ-resistant MM patients as well as those with relapsed MM. Significantly, the expression level of KDM5C exhibits an inverse correlation with the overall survival of MM patients. Moreover, KDM5C is indispensable for MM cell proliferation. Depletion of KDM5C augmented the sensitivity of MM cells to BTZ treatment both in vitro and in vivo. We found that KDM5C forms a novel complex with CBP and MYC via its PHD2 domain. This complex formation triggers lysine 27 acetylation in histone H3 (H3K27ac) and subsequent enrichment of H3K27ac on the PERK promoter. As a result, PERK transcription is activated, and Nrf2 phosphorylation is promoted, bolstering the unfolded protein response within the endoplasmic reticulum of MM cells. In contrast, the methylation status of histone H3 lysine 4 (H3K4me1/3) on the PERK promoter remains unaltered, regardless of the complex state. Taken together, the findings of this study underscore the key role of KDM5C as a driving force behind MM progression and BTZ resistance, indicating that KDM5C represents a novel and promising therapeutic target for the treatment of BTZ-resistant MM.