Abstract
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.
Highlights
Liver cancer, the most common form of which is hepatocellular carcinoma (HCC), is a leading cause of death worldwide [1,2]
PER1 = Short interference RNA (siRNA) PER1-treated macroH2A1 knocked down HepG2 cells; bars, standard error of mean (SEM); * p < 0.05; three biological replicates were each assayed in triplicate and results were expressed as mean ± standard error of mean (SEM)
MacroH2A1 knocked down HepG2 cells; M1 siRNA PER1 = siRNA PER1-treated macroH2A1 knocked down HepG2 cells; bars, standard error of mean (SEM); * p < 0.05; three biological replicates knocked down HepG2 cells; bars, standard error of mean (SEM); * p < 0.05; three biological replicates were each assayed in triplicate and results were expressed as mean ± standard error of mean (SEM)
Summary
The most common form of which is hepatocellular carcinoma (HCC), is a leading cause of death worldwide [1,2]. Biomedicines 2021, 9, 1057 provide only marginal effects [3]. Obesity/metabolic syndrome, currently a pandemic, is a risk factor mainly for HCC among different types of cancer. Obese individuals with a high body mass index (BMI 35–40) had the greatest increase in cancer risk (the risk of HCC was increased by ~5 times) [4]. Obesity is accompanied in more than 90% of cases by non-alcoholic fatty liver disease (NAFLD). NAFLD is the result of an imbalance between the availability of lipids (deriving from the uptake of circulating lipids or from de-novo lipogenesis) and the elimination of lipids (through the oxidation of free fatty acids or the secretion of lipoproteins rich in triglycerides). The natural history of NAFLD in humans is not easy to establish since most studies are retrospective; there is strong and convincing evidence that patients affected by NAFLD have a higher incidence of HCC
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