Targeting Positive Cofactor 4 induces autophagic cell death in MYC-expressing diffuse large B cell lymphoma.

The MYC-expressing diffuse large B-cell lymphoma (DLBCL) is one of the refractory lymphomas. Currently, the pathogenesis of MYC-expressing DLBCL is still unclear, and there is a lack of effective therapy. We characterize that Positive Co-factor 4 (PC4) is an upstream regulator of c-Myc, and PC4 is overexpressed in DLBCL and is closely related to clinical staging, prognosis and c-Myc expression. Further, our in vivo or in vitro studies reveal that PC4 knockdown can induce autophagic cell death and enhance the therapeutic effect of doxorubicin in MYC-expressing DLBCL. And inhibition of c-Myc mediated aerobic glycolysis and activation of AMPK / mTOR signaling pathway are responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Through the DLRTM and EMSA assay, we also find that PC4 exerts its oncogenic functions by directly binding to c-Myc promoters. To sum up, our study provides novel insights into the functions and mechanisms of PC4 in MYC-expressing DLBCL, and suggests that PC4 may be a promising therapeutic target for MYC-expressing DLBCL.