ZMYND8 Reads H3K36me2 to Activate CEBPE Transcription and Suppress Multiple Myeloma Progression through the Inhibition of Adaptive UPR Pathways

Abstract Multiple myeloma (MM) pathogenesis is closely associated with aberrant epigenetic regulation and resulting modifications, such as dimethylation of lysine 36 in histone H3 (H3K36me2). However, the recognition signature of H3K36me2 and its functional role in MM remain largely unknown. Here, the zinc‐finger MYND‐type‐containing 8 (ZMYND8) is identified as a potential reader of the H3K36me2 mark that suppresses MM progression. ZMYND8 knockdown promotes the proliferation and invasion of MM cells. Combined transcriptomic and epigenomic analyses reveal that CCAAT/enhancer‐binding protein epsilon (CEBPE) is a direct downstream target of ZMYND8. CEBPE modulates adaptive unfolded protein response (UPR) pathways through the transcriptional repression of ERN1, XBP1, and ATF6 to impair cell survival. Coimmunoprecipitation and chromatin immunoprecipitation assays show that ZMYND8 activates CEBPE expression in an H3K36me2‐dependent manner and that its Pro‐Trp‐Trp‐Pro domain is required for binding H3K36me2 modules, leading to CEBPE transcription. Low ZMYND8 expression is significantly correlated with adverse clinicopathological features and poor survival outcomes in MM patients. Furthermore, ZMYND8 upregulation increases the sensitivity of MM cells to carfilzomib. Taken together, these findings demonstrate that ZMYND8 epigenetically activates CEBPE transcription and suppresses MM cell growth by inhibiting the adaptive UPR, suggesting that ZMYND8 can be a novel therapeutic target for patients with MM.