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Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer

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Abstract

Gastric cancer (GC), a high mortality malignancy, is induced by genetic and epigenetic factors. DNA and histone methylation play critical roles in tumor suppressor genes inactivation. SRBC (serum deprivation response factor-related gene product that binds to the c-kinase), suggested as a tumor suppressor gene, participates in apoptosis, tumor chemoresistance and DNA damage response and is repressed in various cancers. Inspecting the mechanisms underlying SRBC suppression is important for cancer treatments. We investigated SRBC promoter DNA methylation status and expression of SRBC and EZH2 histone methyltrasferase in gastric cancer. Also, we surveyed SRBC expression after 5-azacitidine and UNC1999 treatments of AGS cell line. In current work, we used gastric adenocarcinoma tissues, marginal samples and normal gastric biopsies. DNA methylation was detected by Methylation- Specific PCR and mRNA expression was measured by Real-Time PCR. SRBC promoter methylation analysis, showed fully and partial methylated versions that were associated with patient’s age (p = 0.001). SRBC expression significantly decreased in GC compare with marginal and normal samples (p-value < 0.001). EZH2 showed remarkable up-regulation in GC than controls and demonstrated a strong inverse correlation with SRBC expression (r = − 0.69). Restoration of SRBC expression was observed after 5-azacitidine and UNC1999 applications with a remarkable increase by combinational treatment. We showed that EZH2 plays role in SRBC silencing in addition to DNA methylation. Our study, suggests that DNA methylation and EZH2 are involved in SRBC silencing and their inhibitors can be considered in cancer treatment investigations to overcome chemoresistance induced by SRBC inactivation.

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Acknowledgements

We would like to thank to staff in Departments of Pathology and Surgery as well as Endoscopy Section in Imam Reza and Shahid Madani hospitals of Tabriz, Tabriz, Iran that kindly contributed with this investigation.

Funding

This work was funded by University of Tabriz, Tabriz, Iran.

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Authors and Affiliations

  1. Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

    Shiva Rezaei, Mohammad Ali Hosseinpourfeizi & Reza Safaralizadeh

  2. Liver and Gastroenterology Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Yaghoub Moaddab

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  1. Shiva Rezaei
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  2. Mohammad Ali Hosseinpourfeizi
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  3. Yaghoub Moaddab
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  4. Reza Safaralizadeh
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Contributions

Conceptualization and Study design: MAHF, RS and SR Patient’s sample provision: YM Experiments: SR Data analysis and interpretation: SR, MAHF and RS Writing—original draft preparation: SR Writing—review and editing: SR, MAHF, YM and RS Funding acquisition: MAHF and RS Supervision: MAHF and RS. All authors read and approved the final manuscript.

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Correspondence to Mohammad Ali Hosseinpourfeizi or Reza Safaralizadeh.

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The authors declare that they have no conflict of interest.

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All participants received and signed an informed written consent. The study was conducted according to the research ethics approved by the committee of Tabriz University of Medical Sciences (Reference Number: IR.TBZMED.REC.1397.772).

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Rezaei, S., Hosseinpourfeizi, M.A., Moaddab, Y. et al. Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer. Mol Biol Rep 47, 5721–5727 (2020). https://doi.org/10.1007/s11033-020-05619-9

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  • DOI: https://doi.org/10.1007/s11033-020-05619-9

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