RESUMO
Oncohistones have emerged as a new area in cancer epigenetics research. Recent efforts to catalogue histone mutations in cancer patients have revealed thousands of histone mutations across different types of cancer. In contrast to previously identified oncohistones (H3K27M, H3G34V/R, and H3K36M), where the mutations occur on the tail domain and affect histone post-translational modifications, the majority of the newly identified mutations are located within the histone fold domain and affect gene expression via distinct mechanisms. The recent characterization of the selected H2B has revealed previously unappreciated roles of oncohistones in nucleosome stability, chromatin accessibility, and chromatin remodeling. This review summarizes recent advances in the study of H2B oncohistones and other emerging oncohistones occurring on other types of histones, particularly those occurring on the histone fold domain.
RESUMO
The recent discovery of the cancer-associated E76K mutation in histone H2B (H2BE76-to-K) in several types of cancers revealed a new class of oncohistone. H2BE76K weakens the stability of histone octamers, alters gene expression, and promotes colony formation. However, the mechanism linking the H2BE76K mutation to cancer development remains largely unknown. In this study, we knock in the H2BE76K mutation in MDA-MB-231 breast cancer cells using CRISPR/Cas9 and show that the E76K mutant histone H2B preferentially localizes to genic regions. Interestingly, genes upregulated in the H2BE76K mutant cells are enriched for the E76K mutant H2B and are involved in cell adhesion and proliferation pathways. We focused on one H2BE76K target gene, ADAM19 (a disintegrin and metalloproteinase-domain-containing protein 19), a gene highly expressed in various human cancers including breast invasive carcinoma, and demonstrate that H2BE76K directly promotes ADAM19 transcription by facilitating efficient transcription along the gene body. ADAM19 depletion reduced the colony formation ability of the H2BE76K mutant cells, whereas wild-type MDA-MB-231 cells overexpressing ADAM19 mimics the colony formation phenotype of the H2BE76K mutant cells. Collectively, our data demonstrate the mechanism by which H2BE76K deregulates the expression of genes that control oncogenic properties through a combined effect of its specific genomic localization and nucleosome destabilization effect.
Assuntos
Proteínas ADAM/genética , Neoplasias da Mama/genética , Histonas/genética , Proteínas ADAM/metabolismo , Neoplasias da Mama/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Histonas/metabolismo , Humanos , Mutação/genética , Nucleossomos , Oncogenes/genética , Polimorfismo de Nucleotídeo Único/genéticaAssuntos
Adenocarcinoma/genética , Anexina A3/genética , Carcinoma Ductal Pancreático/genética , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Movimento Celular/genética , Proliferação de Células/genética , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica/genética , Histonas/genética , Humanos , Proteínas de Neoplasias/genética , Ligação Proteica/genéticaAssuntos
Proteínas de Ligação a DNA/genética , DNA/genética , Histonas/genética , Neoplasias/genética , Proliferação de Células/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , DNA/ultraestrutura , Proteínas de Ligação a DNA/ultraestrutura , Histonas/ultraestrutura , Humanos , Mutação/genética , Neoplasias/patologia , Conformação de Ácido Nucleico , Nucleossomos/genética , Oncogenes/genética , FenótipoRESUMO
Histone modifications are one form of epigenetic information that relate closely to gene regulation. Aberrant histone methylation caused by alteration in chromatin-modifying enzymes has long been implicated in cancers. More recently, recurrent histone mutations have been identified in multiple cancers and have been shown to impede histone methylation. All three histone mutations (H3K27M, H3K36M, and H3G34V/R) identified result in amino acid substitution at/near a lysine residue that is a target of methylation. In the cases of H3K27M and H3K36M, found in pediatric DIPG (diffuse intrinsic pontine glioma) and chondroblastoma respectively, expression of the mutant histone leads to global reduction of histone methylation at the respective lysine residue. These mutant histones are termed "oncohistones" because their expression reprograms the epigenome and shapes an oncogenic transcriptome. Dissecting the mechanism of H3K27M-driven oncogenesis has led to the discovery of promising therapeutic targets in pediatric DIPG. The purpose of this review is to summarize the work done on identifying and dissecting the oncogenic properties of histone H3 mutations.