A Hypoxia-Epigenetics Axis Drives EMT in Pancreatic Cancer

Abstract

Abstract Epithelial-to-mesenchymal transition (EMT) is a classical cellular plasticity process induced by various cell-intrinsic and -extrinsic triggers. Although prominent factors, such as TGFβ, mediate EMT via well-characterized pathways, alternative avenues are less well understood. Transcriptomic subtyping of pancreatic ductal adenocarcinoma (PDAC) has demonstrated that basal-like PDACs enrich a mesenchymal-like expression program, emphasizing the relevance of EMT in the disease. In this issue of Cancer Research, Brown and colleagues demonstrate the tight connection of EMT to hypoxia. Through a detailed mechanistic analysis, the authors deciphered that hypoxia-induced signals are integrated by the histone H3 lysine 36 di-methylation (H3K36me2) mark. On the one hand, hypoxia decreased activity of the H3K36me2 eraser KDM2A, while on the other hand promoting stabilization of the H3K36me2 writer NSD2. Hypoxia diminished the expression of a set of serine-threonine phosphatases, subsequently resulting in SRC kinase family-dependent activation of canonical MEK, ERK, and JNK signaling to impinge on NSD2 expression. In addition, reduced expression of the protein phosphatase PP2Cδ was linked to increased NSD2 protein expression. These discoveries illuminate the close relationship of hypoxia signaling to the epigenetic machinery and cellular plasticity processes. See related article by Brown et al., p. 1764