Table 6 Main histone mutations in cancer
From: The dark side of histones: genomic organization and role of oncohistones in cancer
Histone | Mutations | Preferential genes | Histone domain | Proposed mechanism | Biological evidence | Primary sites of cancer | References |
|---|---|---|---|---|---|---|---|
H2A | E121Q/K/D | Mainly Hist1 cluster | C-TT | Reduced interaction of H2A-H2B dimer with H3-H4 dimer and H2A with linker DNA | None | None | |
R29Q | None | HFD | Interference with residue methylation | None | None | ||
E57Q | HIST1H2AB | HFD | Interference with the structural integrity of the H2A fold | Increased expression of EMT markers (in vitro); increased migratory; and invasive phenotype (in vitro) | Carcinomas of the female tract | [91] | |
H2B | E76K | Mainly Hist1 cluster | HFD | Interference with H2A-H2B interaction; distortion of the interface between H2B and H4 | Enhanced colony formation; cellular proliferation (in vitro); cooperation with mutant PIK3CA to promote colony formation (in vitro) | Bladder cancer, head and neck cancer | |
E113K/Q | None | HFD | Interference with acidic patch at H2A-H2B dimer surface | None | None | ||
F70L | Mainly Hist2 cluster | HFD | Distortion of H2B-H4 interface (adjacent residue E71 is also frequently mutated) | None | None | ||
E2Q/K | None | N-TT | Interference with residue ADP-ribosylation | None | None | ||
G53D | Mainly Hist2 cluster | H HFD | Disruption of H2B-DNA interaction | Increased gap closure ability and transwell migration of cells (in vitro) | Pancreatic ductal adenocarcinoma | ||
S37many | None | HFD | Interference with residue phosphorylation | None | Follicular lymphoma | [93] | |
H3 | K27M | H3F3A (H3.3) | N-TT | Interference with residue methylation (dominant-negative) | Tumor growth and differentiation (in vitro and in vivo); associated with more aggressive tumor phenotype (in patients) | Diffuse intrinsic pontine glioma (pediatric) | [76,77,78,79, 83, 85, 94,95,96,97,98,99,100,101,102,103,104,105,106,107,108] |
K36M | H3F3B (H3.3) | N-TT | Interference with residue methylation (dominant-negative) | Tumor development (in vivo); enhanced colony formation and less sensitivity to apoptotic stimuli (in vitro) | Chondroblastoma (children and young adults) | ||
G34R/V | H3F3A (H3.3) | N-TT | Interference with K36 and K27 methylation (dominant-negative) | None | Cortical pediatric high-grade glioma (young adults) | ||
G34W/L | H3F3A (H3.3) | N-TT | Interference with K36 and K27 methylation (dominant-negative); interference with DNA methylation and histone modifications at heterochromatic and bivalent regions | Enhanced colony formation, infiltration and proliferation (G34W—in vitro and in vivo); reduced differentiation of GCTB stromal cells (primary cells) | Giant cell tumors of bone | ||
E97K | H3.1 genes | HFD | Interference with nucleosome structure | Enhanced colony formation (in vitro) | None | ||
E105K/V | H3B (slight preference) | HFD | Interference with nucleosome structure | None | None | ||
R131C | None | HFD | Interference with nucleosome structure | None | None | ||
H4 | R3C | None | N-TT | Interference with residue symmetric demethylation and citrullination | None | None | |
D68Y/N/H | None | HFD | H2B-H4 interaction | None | None |