Epigenetic Disruption of Histone Deacetylase-2 Accelerated Apoptotic Signaling and Retarded Malignancy in Gastric Cells

Abstract

Background: The objective of this research was to determine whether HDAC2 function is associated with gastric cancer progression. Methods: HDAC2 was knocked out in EPG85.257 cells using CRISPR/Cas9 and tumorigenesis pathways were evaluated. Results: Cell proliferation, colony formation, wound healing and transwell invasion were inhibited in ΔHDAC2:EPG85.257 cells. Quantitative analyses revealed a significant downregulation of MMP1, p53, Bax, MAPK1, MAPK3, pro-Caspase3, ERK1/2, p-ERK1/2, AKT1/2/3, p-AKT1/2/3, p-NF-κB (p65), Twist, Snail and p-FAK transcripts/proteins, while SIRT1, PTEN, p21 and Caspase3 were upregulated in ΔHDAC2:EPG85.257 cells. Conclusion: These results indicated that HDAC2 enhanced migration, colony formation and transmigration ability. HDAC2 inhibition may improve gastric cancer chemotherapy pathways.

Plain language summary

DNA changes are the main causes of cancer. Therefore, finding easy ways to manipulate and correct DNA changes has been the biggest medical concern in cancer treatment. Researchers have introduced CRISPR/Cas9 as the newest technology for gene editing that precisely and easily changes the genome of any cell. In our study, histone deacetylase-2 was disrupted in gastric cancer cells using CRISPR technology. This modification reduced growth kinetics and invasion of cancer cells. On the other hand, cell death (also called apoptosis) was induced. Sensitization of the cancer cells to chemotherapeutic agents is noticeable in this research. This study needs to uncover more signaling pathways in vitro and in vivo.

Tweetable abstract

Epigenetic disruption of histone deacetylase-2 improved gastric cancer chemotherapy and apoptosis signaling, and induced S-phase cell cycle arrest.

Keywords::

• cell proliferation
• cell signaling HDAC2
• CRISPR/Cas9
• gastric cancer
• multidrug resistance

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/epi-2023-0350

Author contributions

SA Mirzaei coordinated the study, designed the experiments, and revised the final manuscript. M Ghatrehsamani, H Yaghoobi and F Elahian were supervisors who participated in laboratory education, data analyses and intellectual discussions of the data. SA Hosseini performed the experiments, analyzed the data and participated in writing the manuscript as part of their PhD dissertation. All authors have reviewed and accepted the final manuscript.

Acknowledgments

The authors acknowledge and appreciate the anonymous reviewers for their thoughtful comments, which helped improve the quality of the article.

Financial disclosure

The authors would like to express gratitude to the Shahrekord University of Medical Sciences (SKUMS-3241) and the Iran National Science Foundation (INSF-98021275) for financial support. The founders had no role in the study design, data collection, analyses, decision to publish or manuscript writing process. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Data sharing statement

The datasets generated and/or analyzed during the current study are available in the DDBJ and NCBI databases with accession numbers LC740576, LC740868, LC740575, and LC740867. Other data are available on request from the corresponding author.

Additional information

Funding

The authors would like to express gratitude to the Shahrekord University of Medical Sciences (SKUMS-3241) and the Iran National Science Foundation (INSF-98021275) for financial support. The founders had no role in the study design, data collection, analyses, decision to publish or manuscript writing process. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.