Positive cofactor 4 (PC4) is a potent upstream regulator of c-Myc, a gene closely associated with treatment resistance in patients with diffuse large B cell lymphoma (DLBCL); therefore, PC4 knockdown could improve outcomes in patients with MYC-expressing DLBCL, according to a recently published study in Experimental Hematology.
Close to 40% of patients with DLBCL are refractory to the standard combination of rituximab and CHOP chemotherapy (R-CHOP) and have a poor prognosis. Previous studies have linked R-CHOP resistance with the expression of several genes, including c-Myc, the researchers noted.However, the lack of drug recognition sites of the c-Myc protein makes it a difficult therapeutic target, they added.
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“As a result, it was critical to identify the c-Myc related targets for precise individualized therapy and better prognosis,” the authors wrote.
To further understand the processes involved in C-Myc upregulation, the authors performed in vitro and in vivo studies which led to the identification of PC4 as a potential oncogene involved in the upregulation of Myc.
Compared to healthy tissue, PC4 mRNA was significantly overexpressed in tumor tissue. Further research revealed PC4 to be significantly overexpressed in c-Myc positive tissues. Similarly, immunohistochemical analysis revealed that PC4 immunohistochemical score was directly correlated with a positive c-Myc cell percentage. Assessment of public cancer databases provided similar results.
An in vitro study involving DLBCL stable cell lines with PC4 knockdown revealed that PC4 knockdown led to cell apoptosis and significant inhibition of cell growth. Posterior examination with transmission electron microscopy showed autophagic vacuole formation in the aforementioned cell lines.
A mouse model designed to study PC4 function in vivo was consistent with the in vitro results, showing that PC4 knockdown significantly reduced tumor size and growth.
To further investigate the mechanisms behind the apoptotic effect of PC4 knockdown on cancerous cells, the authors performed a genome-wide analysis which revealed the AMPK/mTOR signaling pathway to be particularly affected by PC4 knockdown. Metabolism-related experiments suggested PC4 be involved in the production of lactate and ATP in malignant cells as well as in the expression of enzymes involved in glycolysis.
An experiment comparing cell viability after doxorubicin treatment in cancerous cells with PC4 knockdown and controls revealed PC4 knockdown to increase cell sensitivity towards doxorubicin.
“Our study provided novel insights into the functions and mechanisms of PC4 in c-Myc(+) DLBCL and suggested that PC4 may be a therapeutic target for c-Myc(+) DLBCL,” the authors concluded.
Ma L, Gong Q, Chen Y, et al. Targeting positive cofactor 4 induces autophagic cell death in Myc-expressing diffuse large B-cell lymphoma. Expl Hematol. Published online January 13, 2023. doi:10.1016/j.exphem.2023.01.001