DNA Hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression

Francesca Rappa, Francesco Cappello, Valerio Pazienza, Farhad Rezaee, Antonella Agodi, Julien Douet, Michela Borghesan, Concetta Panebianco, Caterina Fusilli, Giovanni Rizzo, Alessandra Warren, Shane Minogue, Jude A. Oben, Illar Pata, Manlio Vinciguerra, Gianluigi Mazzoccoli, Chris Faulkes, John M. Sedivy, Francesco Cappello, Abigail PetersonTommaso Mazza, Marcus Buschbeck

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Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear.macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescentlike phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression.
Lingua originaleEnglish
pagine (da-a)594-606
Numero di pagine13
RivistaCancer Research
Stato di pubblicazionePublished - 2016


All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cita questo

Rappa, F., Cappello, F., Pazienza, V., Rezaee, F., Agodi, A., Douet, J., Borghesan, M., Panebianco, C., Fusilli, C., Rizzo, G., Warren, A., Minogue, S., Oben, J. A., Pata, I., Vinciguerra, M., Mazzoccoli, G., Faulkes, C., Sedivy, J. M., Cappello, F., ... Buschbeck, M. (2016). DNA Hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression. Cancer Research, 76, 594-606.