Targeting positive cofactor 4 induces autophagic cell death in MYC-expressing diffuse large B-cell lymphoma

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 characterized positive cofactor 4 (PC4) as an upstream regulator of c-Myc, and PC4 is overexpressed in DLBCL and is closely related to clinical staging, prognosis, and c-Myc expression. Furthermore, our in vivo and in vitro studies revealed that PC4 knockdown can induce autophagic cell death and enhance the therapeutic effect of doxorubicin in MYC-expressing DLBCL. Inhibition of c-Myc-mediated aerobic glycolysis and activation of the AMPK/mTOR signaling pathway are responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Using dual-luciferase reporter assay and electrophoretic mobility shift assay assays, we also found 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.