The histone variant macroh2a1 impacts circadian gene expression and cell phenotype in an in vitro model of hepatocellular carcinoma
Carbone, Annalucia (Fondazione IRCCS Casa Sollievo della Sofferenza)
De Santis, Elisabetta (Fondazione IRCCS Casa Sollievo della Sofferenza)
Cela, Olga (University of Foggia)
Giambra, Vincenzo (Fondazione IRCCS Casa Sollievo della Sofferenza)
Miele, Luca (Catholic University of the Sacred Heart)
Marrone, Giuseppe (Catholic University of the Sacred Heart)
Grieco, Antonio (Catholic University of the Sacred Heart)
Buschbeck, Marcus (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Capitanio, Nazzareno (University of Foggia)
Mazza, Tommaso (Fondazione IRCCS Casa Sollievo della Sofferenza)
Mazzoccoli, Gianluigi (Fondazione IRCCS Casa Sollievo della Sofferenza)

Data:	2021
Resum:	Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. A foremost risk factor for HCC is obesity/metabolic syndrome-related non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which is prompted by remarkable changes in transcription patterns of genes enriching metabolic, immune/inflammatory, and circadian pathways. Epigenetic mechanisms play a role in NAFLD-associated HCC, and macroH2A1, a variant of histone H2A, is involved in the pathogenesis modulating the expression of oncogenes and/or tumor suppressor genes and interacting with SIRT1, which crucially impacts the circadian clock circuitry. Hence, we aimed to appraise if and how macroH2A1 regulated the expression patterns of circadian genes in the setting of NAFLD-associated HCC. We took advantage of an in vitro model of liver cancer represented by HepG2 (human hepatocarcinoma) cells stably knocked down for macroH2A1 and conducted whole transcriptome profiling and deep phenotyping analysis. We found up-regulation of PER1 along with several deregulated circadian genes, enriching several important pathways and functions related to cancer onset and progression, such as epithelial-to-mesenchymal transition, cell cycle deregulation, and DNA damage. PER1 silencing partially mitigated the malignant phenotype induced by the loss of macroH2A1 in HCC cells. In conclusion, our findings suggest a modulatory role for the core circadian protein PER1 in liver carcinogenesis in the context of a lack of the macroH2A1 epigenetic and transcriptional landscape.
Nota:	Funding: This research was funded by the "5 × 1000" voluntary contribution and by a grant from the Italian Ministry of Health (Ricerca Corrente 2020-2021) to Gianluigi Mazzoccoli and T.M. and by a grant from the Italian Ministry of Health (Ricerca Finalizzata Young-Researcher GR-2016- 02361287) to V.G. The APC were funded by the Italian Ministry of Health (Ricerca Corrente 2020- 2021) to Gianluigi Mazzoccoli.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Circadian ; Cancer ; Biological clock ; HCC ; PER1
Publicat a:	Biomedicines, Vol. 9 Núm. 8 (august 2021) , p. 1057, ISSN 2227-9059

DOI: 10.3390/biomedicines9081057
PMID: 34440260

21 p, 3.3 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Institut de Recerca contra la Leucèmia Josep Carreras
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