Negroni, L. | Search bioRxiv

bioRxiv2019

CHD4 regulates PADI1 and PADI3 expression linking pyruvate kinase M2 citrullination to glycolysis and proliferation.

CHD3 and CHD4 are mutually exclusive ATPase subunits 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 three arginines of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination reprograms 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 defining a novel pathway regulating proliferation of melanoma and other cancer cells. We provide unique insight as to how conversion of arginines to citrulline impacts key interactions within PKM2 that act in concert to reprogram its activity as an additional mechanism regulating this important enzyme.

cancer biology↗

bioRxiv2019

IRE1-UBE2D3 signaling controls the recruitment of myeloid cells to glioblastoma.

Tumor cells are exposed to intrinsic and environmental challenges that trigger endoplasmic reticulum (ER) homeostasis alteration, in turn leading to ER stress. To cope with this, tumor cells engage an adaptive signaling pathway, the unfolded protein response (UPR) thus promoting the acquisition of malignant features. As such, glioblastoma multiforme (GBM), the most aggressive primary brain tumors, exhibit constitutive UPR signals to sustain growth. Herein, we showed that signaling elicited by one of the UPR sensors, IRE1, promotes GBM tumor invasion, angiogenesis and infiltration by macrophages. Hence, high IRE1 activity in tumors predicts worse outcome. We further dissect IRE1-dependent mechanisms that shape the brain tumor immune microenvironment towards myeloid cells. We identify an IRE1-dependent signaling pathway that directly controls the expression/release of proinflammatory chemokines (CXCL2, IL6, IL8) leading to tumor cell-mediated chemoattraction of neutrophils and macrophages. This pathway requires XBP1 non-conventional mRNA splicing and XBP1s-dependent expression of the E2 ubiquitin enzyme UBE2D3. The latter contributes to the degradation of the NF{kappa}B inhibitor I{kappa}B, leading to the up-regulation of proinflammatory chemokines. Our work identifies a novel IRE1/UBE2D3 proinflammatory signaling axis instrumental to pro-tumoral immune regulation of GBM.

cancer biology↗