Macroh2a1 Case Study - 1126 Words

A large amount of data highlighted the different molecular mechanisms the 90 primarily tumor suppressive function of macroH2A1, which was reviewed 91 elsewhere (1, 18). Briefly, current data support a tumour-suppressive role for 92 macroH2A1.1, whereas the function of macroH2A1.2 is dependent on the specific 93 cancer context (18). MacroH2A1 expression often is downregulated as disease 94 progresses or when the tumor is de-differentiated; its artificial over-expression 95 reduces the metastatic potential of melanoma and hepatocellular carcinoma (HCC) 96 (13, 20, 21), whereas siRNA-mediated depletion of macroH2A1 was shown to 97 increase the aggressiveness of HCC, teratoma and breast cancer cells (15, 20, 22). 98 This could be due to the†¦show more content†¦These results highlight the independence of cellular senescence 117 from epigenetic aging. In senescent cells, specialized domains of transcriptionally 118 silent senescence-associated heterochromatic foci (SAHF), contain ing 119 heterochromatin proteins such as HP1, are thought to repress expression of 120 proliferation-promoting genes. Early investigation of the composition and mode of 121 assembly of SAHF and its contribution to cell cycle exit, led to the identification of 122 enrichment in macroH2A1 (30). Chromatin regulators, HIRA and ASF1a drive 123 formation of macroH2A1-containing SAHF and senescence-associated cell cycle 124 exit (30). 125 MacroH2A1 incorporation occurs as a late step and only after SAHF appearance by 126 DAPI staining (31). MacroH2A1 isoforms are thus highly expressed in cells 127 undergoing senescence, which is an antitumor mechanism, suggesting macroH2A1, 128 and in particular macroH2A1.1, may be a useful biomarker for senescent cells in 129 tumors such as lung and colon cancer (25, 32). MacroH2A1 seems to be 130 mechanistically dispensable for RS and DIS, as the number of ï  ¢-galactosidase 131 positive cells in the liver of aged macroH2A1 knock-out (KO) mice is identical to the 132 ones of aged matched wild type littermates, as well as in H2O2-treated hepatoma 133 cells KO for macroH2A1 compared to control cells (13). As said,