Aflatoxin-induced upregulation of protein arginine methyltransferase 5 is mediated by protein kinase C and extracellular signal-regulated kinase

Abstract

Aflatoxins are fungal metabolites classified into four major groups such as B 1 , B 2 , G 1 , and G 2 . These natural aflatoxins are designated as group I carcinogen by the International Agency for Research on Cancer. Among these, the aflatoxin B 1 is more potent. Protein arginine methyltransferase 5, an epigenetic modulator, emerged as an oncoprotein, is overexpressed in diverse forms of cancers. The present study aims to explore the AFB 1 -mediated overexpression of PRMT5. The AFB 1 at nanomolar concentrations increased the cell viability, as well as the expression of PRMT5 and its binding partner methylosome protein 50 level significantly in L-132 and HaCaT cells. The knockdown of PRMT5 by its siRNA is attenuated by AFB 1 , thus substantiating AFB 1 -mediated PRMT5 overexpression. The PKC isoform-specific inhibitor study revealed direct relation with PKCα and an inverse relation with PKCδ. The analysis of mitogen-activated protein kinase pathway revealed reduced p38 phosphorylation with increased phosphorylation of ERK1/2 upon exposure to AFB 1 . The combination of MEK and PKC inhibitors with AFB 1 treatment revealed that PKCα activates downstream kinase ERK which leads to overexpression of PRMT5. In summary, we propose that PKCα and extracellular signal-regulated kinases are conjointly involved in the induction of PRMT5 upon AFB 1 exposure.