Epigenomic Reordering Induced by Polycomb Loss Drives Oncogenesis but Leads to Therapeutic Vulnerabilities in Malignant Peripheral Nerve Sheath Tumors

Abstract

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with recurrent loss-of-function alterations in polycomb-repressive complex 2 (PRC2), a histone-modifying complex involved in transcriptional silencing. To understand the role of PRC2 loss in pathogenesis and identify therapeutic targets, we conducted parallel global epigenomic and proteomic analysis of archival formalin-fixed, paraffinembedded (FFPE) human MPNST with and without PRC2 loss (MPNST LOSS vs. MPNST RET). Loss of PRC2 resulted in increased histone posttranslational modifications (PTM) associated with active transcription, most notably H3K27Ac and H3K36me2, whereas repressive H3K27 di-and trimethylation (H3K27me2/3) marks were globally lost without a compensatory gain in other repressive PTMs. Instead, DNA methylation globally increased in MPNST LOSS. Epigenomic changes were associated with upregulation of proteins in growth pathways and reduction in IFN signaling and antigen presentation, suggesting a role for epigenomic changes in tumor progression and immune evasion, respectively. These changes also resulted in therapeutic vulnerabilities. Knockdown of NSD2, the methyltransferase responsible for H3K36me2, restored MHC expression and induced interferon pathway expression in a manner similar to PRC2 restoration. MPNST LOSS were also highly sensitive to DNA methyltransferase and histone deacetylase (HDAC) inhibitors. Overall, these data suggest that global loss of PRC2mediated repression renders MPNST differentially dependent on DNA methylation to maintain transcriptional integrity and makes them susceptible to therapeutics that promote aberrant transcription initiation. Significance: Global profiling of histone PTMs and protein expression in archival human MPNST illustrates how PRC2 loss promotes oncogenesis but renders tumors vulnerable to pharmacologic modulation of transcription. See related commentary by Natarajan and Venneti, p. 3172

Bivalent promoter hypermethylation in cancer is linked to the H327me3/H3K4me3 ratio in embryonic stem cells

“…An alternative model is direct interference with Polycomb function, which also occurs in many cancers and may lead to hypermethylation [69][70][71]. Our analysis of mESC Polycomb mutants supports a causal association: inactivation of the PRC1.1 variant component Kdm2b leads to significant Fig.…”

The Role of Polycomb Repressive Complex in Malignant Peripheral Nerve Sheath Tumor

“…It is unclear whether these observations are due to alteration of these pathways in the tumor cells or through the reduction of tumor-infiltrating antigen-presenting cells within the tumor. Finally, PRC2 loss was noted to correlate with global DNA hypermethylation at gene promoters and intergenic regions [62]. This DNA hypermethylation was hypothesized by the authors as a potential explanation for the repression of protein expression in the absence of functional PRC2 in MPNSTs.…”

“…The identification of IHC screening for H3K27me3 as a reliable biomarker of MPNST led to additional studies that utilized H3K27me3 IHC as a diagnostic marker for MPNST [54][55][56][57][58][59][60][61]. Wojcik and colleagues used this screen to select samples of both PRC2 mutant and PRC2 wildtype status for use in proteomic analyses [62]. These proteomic analyses revealed that the loss of PRC2 caused global changes in post-translational modifications of histones, including 1) a substantial decrease in the transcriptionally repressive modification H3K27me3, 2) broad distribution of the repressive marker H3K27me2, 3) no compensatory gain of other repressive markers, for instance H3K9me3 or H4K20me3, and 4) significant increase in active chromatin markers, including H3K27 acetylation (H3K27ac) and H3K36me2 [62].…”

“…Wojcik and colleagues used this screen to select samples of both PRC2 mutant and PRC2 wildtype status for use in proteomic analyses [62]. These proteomic analyses revealed that the loss of PRC2 caused global changes in post-translational modifications of histones, including 1) a substantial decrease in the transcriptionally repressive modification H3K27me3, 2) broad distribution of the repressive marker H3K27me2, 3) no compensatory gain of other repressive markers, for instance H3K9me3 or H4K20me3, and 4) significant increase in active chromatin markers, including H3K27 acetylation (H3K27ac) and H3K36me2 [62]. Furthermore, they identified that the loss of H3K27me3 across the genome led to the occupancy of those histone tails solely by H3K36me2.…”

“…In addition to the upregulation of recognized PRC2 targets, loss of PRC2 has been implicated in the upregulation of generalized growth and cell division pathways, nucleosome remodeling, and transcriptional activation [18,62]. Somewhat surprisingly, due to the transcriptionally repressive role of PRC2, loss of this complex has also been identified as correlating with the downregulation of certain pathways, including immune-related signaling such as interferon (IFN) signaling and antigen presentation [62]. It is unclear whether these observations are due to alteration of these pathways in the tumor cells or through the reduction of tumor-infiltrating antigen-presenting cells within the tumor.…”