Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation

Abstract

Chromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the Nucleosome Remodelling and Deacetylation (NuRD) complex that regulates gene expression. CHD4 is essential for growth of multiple patient derived melanoma xenografts and for breast cancer. Here we show that CHD4 regulates expression of PADI1 (Protein Arginine Deiminase 1) and PADI3 in multiple cancer cell types modulating citrullination of arginine residues of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination of PKM2 R106 reprogrammes cross-talk between PKM2 ligands lowering its sensitivity to the inhibitors Tryptophan, Alanine and Phenylalanine and promoting activation by Serine. Citrullination thus bypasses normal physiological regulation by low Serine levels to promote excessive glycolysis and reduced cell proliferation. We further show that PADI1 and PADI3 expression is up-regulated by hypoxia where PKM2 citrullination contributes to increased glycolysis. We provide insight as to how conversion of arginines to citrulline impacts key interactions within PKM2 that act in concert to reprogramme its activity as an additional mechanism regulating this important enzyme.

Functional analysis of recurrent non-coding variants in human melanoma

“…To refine our search space, we collated 69 previously published ChIP-seq and ATAC-seq datasets that were specifically performed on melanoma or melanocyte samples 18,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] (Supplemental Table 1). We reasoned these regions of the genome are more likely to bind transcription/chromatin factors and refer to them as putative melanoma regulatory regions (pMRRs).…”

A prognostic Risk Score model for oral squamous cell carcinoma constructed by 6 glycolysis-immune-related genes

“…However, few HRG related studies were found in OSCC. The PADI3 has anticancer effect through the arresting of cell cycle in colon cancer, and it regulates the glycolysis in multiple cancer cell types [ 44 ]. The MIPOL1 may induce tumor suppression in nasopharyngeal carcinoma resulting anticancer effect [ 45 ].…”

The virtues and vices of protein citrullination

“…A study published last year showed that PADI1- and PADI3-mediated citrullination of the glycolytic enzyme pyruvate kinase M2 (PKM2) alters its binding to amino acids and promotes glycolysis in cancer cells [ 96 ]. A more recent study showed that citrullination of glukokinase leads to reduction of its catalytic activity and results in reduced insulin secretion in response to glucose stimulation [ 97 ].…”