Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression

Abstract

Epithelial plasticity -reversible modulation of a cell's epithelial and mesenchymal features -is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. While different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation underlies epithelial plasticity remains largely unknown. Here, through targeted CRISPR-Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-mesenchymal identity, tumor differentiation, and metastasis. Using a K-to-M histone mutant to directly inhibit H3K36me2, we found that global modulation of the mark is a conserved mechanism underlying the mesenchymal state in various contexts. Mechanistically, regulation of H3K36me2 reprograms enhancers associated with master regulators of epithelialmesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer. STATEMENT OF SIGNIFICANCEAlthough epithelial plasticity contributes to cancer metastasis and chemoresistance, no strategies exist for pharmacologically inhibiting the process. Here, we show that global regulation of a specific histone mark, H3K36me2, is a universal epigenome-wide mechanism that underlies EMT and MET in carcinoma cells. These results offer a new strategy for targeting epithelial plasticity in cancer. Research.on August 5, 2020.

Epigenome dysregulation resulting from NSD1 mutation in head and neck squamous cell carcinoma

“…5a, Supplementary Table 3). Most of these molecular signatures are consistent with previously reported roles of NSD1/H3K36me2 in immune response 20 , epithelial-mesenchymal transition (EMT) 48-51 , and regulation of RAS signaling 52,53 . Our analysis suggests that NSD1 mutations may facilitate HNSCC development through its pleiotropic effects on tumor immunity, signaling, and plasticity.…”

“…In cells that naturally carry the 4;14 translocation that drives overexpression of NSD2 , reducing NSD2 levels results in depletion of intergenic H3K36me2 domains, decreased enhancer activity, and downregulation of target gene expression within topologically associated chromatin domains. In pancreatic carcinoma, Yuan et al 51 found opposing effects of disruption of NSD2 and the lysine-specific demethylase KDM2A and concluded that the NSD2-associated reduction of H3K36me2 results in loss of enhancer activity of a specific class of enhancers that regulate EMT.…”

“…Similarly, NSD2-mediated H3K36me2 has been shown to contribute to KRAS transcriptional program in lung cancers 53 . NSD2 has also been implicated in promoting EMT in pancreatic carcinoma 51 , prostate cancer, renal cell carcinoma, and multiple myelomas 48-50 . A marked downregulation of immune response appeared as one of the most consistent trends across various analyses that we have conducted.…”

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

“…The reduced H3K36me2 but increased H3K36me3 levels in the metastatic 4C11+ cell line are in agreement with the correlation of these marks in colorectal cancer with poor prognosis and lymph node metastasis, respectively [70]. The regulation of H3K36me2 was recently involved with metastatic progression and mesenchymal state during EMT [71]. The increased expression of the H3K36 demethylase Kdm2b in the mesenchymal cell lines, followed by a downregulation in 4C11+ cells, points to the involvement of this enzyme in the decreased H3.3K36me3 levels during EMT.…”

H3K36 Methylation Reprograms Gene Expression to Drive Early Gametocyte Development in Plasmodium Falciparum

“…Our approach allowed for the delineation of genomic regions dynamically occupied by H3K36me2&3 during gametocytogenesis and demonstrate that their stage II gametocyte-speci c abundance (11) manifests as wide-spread, yet largely intergenic, enrichment that is congruent with the characteristic patterns of these hPTMs when functioning repressively in other organisms, particularly during cellular differentiation (76)(77)(78)(79)(80)(81)(82)(83)(84). In line with this, we show that H3K36me2&3 enrichment in stage II gametocytes is associated with an active repression of transcription.…”