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

Lucija Belužić,Eduard Sabidó,Nevenka Kopjar,Robert Belužić,Hyun Kyung Kong,Adriana Lepur,Jong Hoon Park,Filip Rokić,Ivanka Jerić,Guadalupe Espadas,Oliver Vugrek,Ivana Grbeša,Lidija Brkljačić

doi:10.1038/s41598-018-32356-8

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.

Highlights

Functional connections between S-adenosylhomocysteine hydrolase (AHCY) activity and cancer have been reported
AHCY deficiency has been implicated in hepatic pathology of AHCY during the past decade[25], and a recently reported case of hepatocellular carcinoma in an adult[26] allowed us to examine the role of AHCY and its mechanism of action in the cell cycle, cellular proliferation and the DNA damage response in a suitable cell line, such as HepG2
We have presented a mechanism that connects AHCY activity, DNA damage and cell cycle regulation through adenosine levels and draw two major conclusions, which may lead to a refinement of therapeutic procedures for liver cancer as a result of AHCY malfunction and a potentially new approach for targeted cancer therapy based on adenosine depletion

Summary

Introduction

Functional connections between S-adenosylhomocysteine hydrolase (AHCY) activity and cancer have been reported. Several studies noted the connections between AHCY and cancer from various standpoints: as a player that possibly regulates the cancer phenotype[12,13,14], as a druggable candidate[15], or as a promising biomarker[16,17,18,19] Based on these reports, the involvement of AHCY in the molecular mechanisms of cancer is undisputable. AHCY deficiency has been implicated in hepatic pathology of AHCY during the past decade[25], and a recently reported case of hepatocellular carcinoma in an adult[26] allowed us to examine the role of AHCY and its mechanism of action in the cell cycle, cellular proliferation and the DNA damage response in a suitable cell line, such as HepG2. Despite the well-described metabolomic parameters in previous research on AHCY deficiency, one question remains unsolved: What are the implications of adenosine, the primary product of AHCY hydrolytic activity, but not homocysteine, on the cellular metabolism?

Methods

Results

Conclusion