Metabolic perturbation of epigenome by inhibiting S-adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells

Abstract

Cellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage response to endogenous genotoxic stress or DNA-damaging agents. Therefore, targeting the maintenance of compacted chromatin in cancer cells represents an optional intervention to improve the therapeutic efficacy in cancer treatment. Given a crosstalk between methionine cycle and histone methylation, we hypothesize that pharmacologically disrupting methylation potential, defined as the ratio of cellular S-adenosylmethionine to S-adenosylhomocysteine, could affect the chromatin structures in cancer cells and thus enhance their sensitivity to DNA damage response signaling. Our results showed that 3-deazaneplanocin A, a chemical inhibitor of S-adenosylhomocysteine hydrolase, elicited a typical cellular senescence in hepatoma cells. Therapy-induced senescence by 3-deazaneplanocin A was mediated through p53–p21 pathway and triggered by enhanced ataxia-telangiectasia mutated activation related to chromatin changes. In conclusion, our study demonstrated that metabolic perturbation of chromatin status in oncogene-activated cancers could be an optional intervention to sensitize DNA damage response signaling.

The Antitumoral Effect of the S-Adenosylhomocysteine Hydrolase Inhibitor, 3-Deazaneplanocin A, is Independent of EZH2 but is Correlated with EGFR Downregulation in Chondrosarcomas

“…Mechanistically, we demonstrated that DZNep induced apoptosis without inducing γH2AX, a biomarker for DNA damage [23]. Similar observations was done in other studies [7,24], while another study reported that DZNep increases γH2AX in hepatoma cells [25]. Interestingly, we identified EGFR as putative mediators of DZNep induced-apoptosis.…”

Knock-down of AHCY and depletion of adenosine induces DNA damage and cell cycle arrest

“…4A ) suggested a significant increase in double-stranded DNA breaks, which is in agreement with the immunoblotting results that indicate the activation of the protein kinase ATM within the DDR signalling cascade. Other studies show possible connections between AHCY and DNA damage; however, the approaches were based on small molecule inhibitors of AHCY 20 , 35 .

Figure 4 yH2AX spread analysis.

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“…Based on these reports, the involvement of AHCY in the molecular mechanisms of cancer is undisputable. Recently, AHCY-driven mechanisms have been discussed, such as the treatment of liver carcinoma cells (HepG2) with AHCY inhibitors, where the DNA damage response is predicted to be enhanced by endogenous genotoxicity due to DNA damage and subsequent perturbation of the cellular epigenome 20 ; however, the mechanisms by which AHCY affects cancer are still elusive. Additionally, in regard to research on HepG2, most studies evaluated the genotoxicity of many direct and indirect mutagens and compounds with unknown or poorly known mechanisms of action 21 – 24 , thus leaving many questions unanswered.…”

Bioinformatics analysis of aberrantly methylated-differentially expressed genes and pathways in hepatocellular carcinoma

“…In view of the analysis in DAVID, Hyper-LGs in HCC, GO enrichment analysis demonstrated BP included response to endogenous and hormone stimulus, cell surface receptor linked signal transduction, and behavior. One fundamental endogenous genotoxic stimulus could cause DNA damage response in cancers[ 19 ]. MF enrichment indicated glycosaminoglycan, pattern and polysaccharide binding, and protein tyrosine kinase activity.…”