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

Abstract

Recently, functional connections between S-adenosylhomocysteine hydrolase (AHCY) activity and cancer have been reported. As the properties of AHCY include the hydrolysis of S-adenosylhomocysteine and maintenance of the cellular methylation potential, the connection between AHCY and cancer is not obvious. The mechanisms by which AHCY influences the cell cycle or cell proliferation have not yet been confirmed. To elucidate AHCY-driven cancer-specific mechanisms, we pursued a multi-omics approach to investigate the effect of AHCY-knockdown on hepatocellular carcinoma cells. Here, we show that reduced AHCY activity causes adenosine depletion with activation of the DNA damage response (DDR), leading to cell cycle arrest, a decreased proliferation rate and DNA damage. The underlying mechanism behind these effects might be applicable to cancer types that have either significant levels of endogenous AHCY and/or are dependent on high concentrations of adenosine in their microenvironments. Thus, adenosine monitoring might be used as a preventive measure in liver disease, whereas induced adenosine depletion might be the desired approach for provoking the DDR in diagnosed cancer, thus opening new avenues for targeted therapy. Additionally, including AHCY in mutational screens as a potential risk factor may be a beneficial preventive measure.

PulseDIA: in-depth data independent acquisition mass spectrometry using enhanced gas phase fractionation

“…The PulseDIA identified several dysregulated proteins which were absent in the DIA analysis, including NQO1, AHCY, MCC and MYEF2. NQO1 have been reported over-expressed in CCA 33 , and AHCY was associated with adult onset hepatocellular carcinoma 34 , supporting our PulseDIA-based analysis.…”

Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia

“…The inhibition of AHCY expression is mediated by epigenetic mechanism involving gene-specific DNA hypermethylation and enrichment of the gene promoter occupancy by H3K27me3 and deacetylated histone H4K16 [75]. Diminished AHCY activity causes depletion of adenosine, which activates the DNA damage response, leading to cell cycle arrest, decreased proliferation, and DNA damage in hepatocellular carcinoma cells [37].…”

“…DNA and histone modifications as well as microRNAs and circular RNAs have been identified to have a crucial role in the progression of atherosclerosis [26,33], play an important role in stroke pathogenesis [34], Alzheimer’s disease (AD) development [35], neural tube defects [36], and cancer [37]. In this review we summarize the recent progress in studies of epigenetic dysregulation of gene expression by HHcy and its role in the etiology of human disease.…”

Acquired resistance to DZNep-mediated apoptosis is associated with copy number gains of AHCY in a B-cell lymphoma model

“…The direct inhibition of AHCY by DZNep leads to the build-up of the substrate SAH, which in turn causes a negative feedback inhibition of methyltransferases such as EZH2 [22]. Proper functioning of AHCY is essential for the efficient maintenance of histone methylation levels in the cell [23]. Alterations in AHCY function have been linked to cancer with varying outcomes depending on the cancer entity involved.…”

“…For example, with lowered AHCY activity, the invasiveness of breast cancer and glioblastoma cell lines decreases [24,25]. Furthermore, in hepatocellular carcinoma cells, reduced AHCY activity is associated with cell cycle inhibition and a lowered proliferation rate [23]. In esophageal squamous cell carcinoma, however, elevated AHCY levels had no effect on cell proliferation but promoted apoptosis and inhibited cell migration and adhesion [26].…”