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

Cell Biol Toxicol. 2019 Feb;35(1):67-80. doi: 10.1007/s10565-018-9439-8. Epub 2018 Jul 6.


Aflatoxins are fungal metabolites classified into four major groups such as B1, B2, G1, and G2. These natural aflatoxins are designated as group I carcinogen by the International Agency for Research on Cancer. Among these, the aflatoxin B1 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 AFB1-mediated overexpression of PRMT5. The AFB1 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 AFB1, thus substantiating AFB1-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 AFB1. The combination of MEK and PKC inhibitors with AFB1 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 AFB1 exposure.

Keywords: Aflatoxin B1; Arginine methylation; Aspergillus; ERK; PKC; PRMT5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Aflatoxins / toxicity*
  • Cell Line
  • Cell Survival / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Protein Isoforms / metabolism
  • Protein Kinase C / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Up-Regulation / drug effects*


  • Adaptor Proteins, Signal Transducing
  • Aflatoxins
  • MEP50 protein, human
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases