The H3K36me2 writer-reader dependency in H3K27M-DIPG

Abstract

Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.

The LEDGF/p75 Integrase Binding Domain Interactome Contributes to the Survival, Clonogenicity, and Tumorsphere Formation of Docetaxel-Resistant Prostate Cancer Cells

“…Our observation that knockdown of HRP2, as well as JPO2, robustly abrogated the survival, clonogenicity, and tumorsphere formation capacity of DTX-resistant cells implicates for the first time these proteins in the survival of chemoresistant PCa cells. These results are consistent with recent studies showing that depletion of LEDGF/p75 sensitizes mixed-lineage leukemic cells to chemoresistance and that individual or combined silencing of LEDGF/p75 and HRP2 reduces the in vivo growth of treatment-resistant glioma [15,62].…”

KDM4C Contributes to Trophoblast-like Stem Cell Conversion from Porcine-Induced Pluripotent Stem Cells (piPSCs) via Regulating CDX2

“…Previous studies evaluating H3K36me2 observed inconsistent results for recruiting DNMT3A and shaping the intergenic DNA methylation landscape [ 19 ]. Moreover, H3K36me2 could demarcate PRC2-mediated H3K27me2 and H3K27me3 domains in ESCs [ 20 , 21 ]. However, the functions of H3K36me2 in piPSCs and TSCs are unknown.…”

Structural and functional specificity of H3K36 methylation

“…NSD2 overexpression is linked with tumor aggressiveness [ 96 ] in cancers of the breast [ 97 ], cervix [ 98 ], lung [ 99 ], kidney [ 100 ], head and neck [ 101 ], brain [ 91 ], blood [ 102 ], colorectum [ 103 ], prostate, skin [ 96 ], and ovary [ 24 ]. Carcinogenesis associated with changes in the expression of NSD2 is also linked with cell cycle dysregulation [ 102 ], VEGF-A-mediated angiogenesis [ 104 ], hematopoietic stem cell differentiation [ 105 ], metastasis [ 91 ], chemoresistance (in osteosarcoma) [ 106 ], and the expression of various oncogenes (e.g., SYK , PTPN13 and ETV5 in multiple myeloma) [ 107 ].…”

“…NSD2 overexpression is linked with tumor aggressiveness [ 96 ] in cancers of the breast [ 97 ], cervix [ 98 ], lung [ 99 ], kidney [ 100 ], head and neck [ 101 ], brain [ 91 ], blood [ 102 ], colorectum [ 103 ], prostate, skin [ 96 ], and ovary [ 24 ]. Carcinogenesis associated with changes in the expression of NSD2 is also linked with cell cycle dysregulation [ 102 ], VEGF-A-mediated angiogenesis [ 104 ], hematopoietic stem cell differentiation [ 105 ], metastasis [ 91 ], chemoresistance (in osteosarcoma) [ 106 ], and the expression of various oncogenes (e.g., SYK , PTPN13 and ETV5 in multiple myeloma) [ 107 ]. Gain-of-function mutations (E1099K and T1150A) in the SET domain of NSD2 have been associated with the enhanced enzymatic activity of NSD2 in mantle cell lymphoma and pediatric acute lymphoblastic leukemia, in which they cause destabilization of the auto-inhibitory loop responsible for keeping signaling in check (refer below) [ 108 , 109 ].…”