Polycomb-like Protein 3 induces proliferation and drug resistance in multiple myeloma and is regulated by miRNA-15a.

Multiple myeloma (MM) remains incurable due to the persistence of a minor population of MM cells that exhibit drug resistance, which leads to relapse and refractory MM. Elucidating the mechanism underlying drug resistance and developing an effective treatment are critical for clinical management of MM. Here we showed that promoting expression of the gene for polycomb-like protein 3 (PHF19) induced MM cell growth and multi-drug resistance in vitro and in vivo. PHF19 was overexpressed in high-risk and drug-resistant primary cells from patients. High levels of PHF19 were correlated with inferior survival of MM patients, in the total therapy 2 (TT2) cohort and in the Intergroup Francophone du Myeloma (IFM) cohort. Enhancing PHF19 expression levels increased Bcl-xL, MCL-1 and HIF-1a expression in MM cells. PHF19 also bound directly with EZH2 and promoted the phosphorylation of EZH2 through PDK1/AKT signaling. miR-15a is a small non-coding RNA that targeted the 3'UTR of PHF19. We found that downregulation of miR-15a led to high levels of PHF19 in MM cells. These findings revealed that PHF19 served a crucial role in MM proliferation and drug resistance and suggested that the miR-15a/PHF19/EZH2 pathway made a pivotal contribution to MM pathogenesis, offering a promising approach to MM treatment. Implications: Our findings identify that PHF19 mediates EZH2 phosphorylation as a mechanism of myeloma cell drug resistance, providing a rationale to explore therapeutic potential of targeting PHF19 in relapsed or refractory MM patients.