S-Adenosylmethionine Treatment of Colorectal Cancer Cell Lines Alters DNA Methylation, DNA Repair and Tumor Progression-Related Gene Expression.

Sára Zsigrai,Barbara K Barták,Orsolya Pipek,Anna Medgyes-Horváth,Béla Molnár,Gábor Valcz,Zsófia B Nagy,Titanilla Dankó,Vanessza Szabó,Zsolt Tulassay,Péter Igaz,Anna Sebestyén,István Csabai,Alexandra Kalmár,Gábor Barna,István Takács,Krisztina A Szigeti,Orsolya Galamb

doi:10.3390/cells9081864

Sára Zsigrai, Barbara K Barták + Show 16 more

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https://doi.org/10.3390/cells9081864

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Abstract

Global DNA hypomethylation is a characteristic feature of colorectal carcinoma (CRC). The tumor inhibitory effect of S-adenosylmethionine (SAM) methyl donor has been described in certain cancers including CRC. However, the molecular impact of SAM treatment on CRC cell lines with distinct genetic features has not been evaluated comprehensively. HT-29 and SW480 cells were treated with 0.5 and 1 mmol/L SAM for 48 h followed by cell proliferation measurements, whole-genome transcriptome and methylome analyses, DNA stability assessments and exome sequencing. SAM reduced cell number and increased senescence by causing S phase arrest, besides, multiple EMT-related genes (e.g., TGFB1) were downregulated in both cell lines. Alteration in the global DNA methylation level was not observed, but certain methylation changes in gene promoters were detected. SAM-induced γ-H2AX elevation could be associated with activated DNA repair pathway showing upregulated gene expression (e.g., HUS1). Remarkable genomic stability elevation, namely, decreased micronucleus number and comet tail length was observed only in SW480 after treatment. SAM has the potential to induce senescence, DNA repair, genome stability and to reduce CRC progression. However, the different therapeutic responses of HT-29 and SW480 to SAM emphasize the importance of the molecular characterization of CRC cases prior to methyl donor supplementation.

Highlights

Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death according to a Globocan 2018 survey [1].It is believed that in the case of CRC, tumor initiation and progression are the results of acquired genetic and epigenetic alterations during a series of cell divisions [2,3]
The impact of SAM treatment on the proliferation of HT-29 and SW480 cell lines was measured with sulforhodamine B (SRB) assay
Our results showed that SAM inhibited cell growth significantly (p ≤ 0.005) in a concentration-dependent manner in both cell lines (HT-29ctrl : 98.08 ± 9.71%, HT-290.5 : 76.93 ± 4.48%, HT-291 : 69.54 ± 7.63%; SW480ctrl : 100.98 ± 10.88%, SW4800.5 : 79.00 ± 16.11%, SW4801 : 71.54 ± 21.67%)

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death according to a Globocan 2018 survey [1]. It is believed that in the case of CRC, tumor initiation and progression are the results of acquired genetic and epigenetic alterations during a series of cell divisions [2,3]. Besides the application of the TNM staging system or defining major mutations (e.g., KRAS, BRAF), the classification of CRC based on molecular traits can help to predict prognosis and therapy response [1,5]. CRC can be classified into four different consensus molecular subtypes (CMS) based on gene expression alterations. CMS1 is the “MSI immune” subgroup, CMS2 is the “canonical”, CMS3 is the “metabolic”

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