Genomic pathway analysis reveals that EZH2 and HDAC4 represent mutually exclusive epigenetic pathways across human cancers

Abstract

BackgroundAlterations in epigenetic marks, including methylation or acetylation, are common in human cancers. For many epigenetic pathways, however, direct measures of activity are unknown, making their role in various cancers difficult to assess. Gene expression signatures facilitate the examination of patterns of epigenetic pathway activation across and within human cancer types allowing better understanding of the relationships between these pathways.MethodsWe used Bayesian regression to generate gene expression signatures from normal epithelial cells before and after epigenetic pathway activation. Signatures were applied to datasets from TCGA, GEO, CaArray, ArrayExpress, and the cancer cell line encyclopedia. For TCGA data, signature results were correlated with copy number variation and DNA methylation changes. GSEA was used to identify biologic pathways related to the signatures.ResultsWe developed and validated signatures reflecting downstream effects of enhancer of zeste homolog 2(EZH2), histone deacetylase(HDAC) 1, HDAC4, sirtuin 1(SIRT1), and DNA methyltransferase 2(DNMT2). By applying these signatures to data from cancer cell lines and tumors in large public repositories, we identify those cancers that have the highest and lowest activation of each of these pathways. Highest EZH2 activation is seen in neuroblastoma, hepatocellular carcinoma, small cell lung cancer, and melanoma, while highest HDAC activity is seen in pharyngeal cancer, kidney cancer, and pancreatic cancer. Across all datasets studied, activation of both EZH2 and HDAC4 is significantly underrepresented. Using breast cancer and glioblastoma as examples to examine intrinsic subtypes of particular cancers, EZH2 activation was highest in luminal breast cancers and proneural glioblastomas, while HDAC4 activation was highest in basal breast cancer and mesenchymal glioblastoma. EZH2 and HDAC4 activation are associated with particular chromosome abnormalities: EZH2 activation with aberrations in genes from the TGF and phosphatidylinositol pathways and HDAC4 activation with aberrations in inflammatory and chemokine related genes.ConclusionGene expression patterns can reveal the activation level of epigenetic pathways. Epigenetic pathways define biologically relevant subsets of human cancers. EZH2 activation and HDAC4 activation correlate with growth factor signaling and inflammation, respectively, and represent two distinct states for cancer cells. This understanding may allow us to identify targetable drivers in these cancer subsets.

Histone deacetylase 4 increases progressive epithelial ovarian cancer cells via repression of p21 on fibrillar collagen matrices

“…It has been reported that microenvironmental changes play a role in regulating cell behavior, which eventually causes epigenetic disorders in cancer cells (34,35). Additionally, we found that both protein and mRNA of p21 are suppressed when epithelial ovarian cancer cells are seeded on fibrillar collagen.…”

Histone deacetylase 4 promotes cholestatic liver injury in the absence of prohibitin‐1

“…Activity of HDAC is generally linked to transcriptional repression . The misbalance in HDAC activity is associated with cancer and several disorders including fibrosis, with aberrations in inflammatory and chemokine‐related genes . Specifically, HDAC4 has been related to fibrogenesis in vivo and, as we mentioned before, in PBC patients with low expression of PHB1.…”

Tumour Expression of Histone Deacetylases in Uveal Melanoma

“…We observed that HDAC4 expression was strongest for the cytoplasmic area and intensity in uveal melanoma. HDAC4 is often upregulated in malignancies with excess inflammation and chemokine signalling [30], consistent with an inflammatory phenotype known to enhance the progression of uveal melanoma [31]. In some immune cells, controlled nuclear export of HDAC4 plays an important role in cytokine production [28].…”