Synergistic effect of epigenetic inhibitors decitabine and suberoylanilide hydroxamic acid on colorectal cancer in vitro

Abstract

Colorectal cancer (CRC) is major public health burden and a common cause of oncological deaths worldwide. Alterations of the epigenetic landscape are a well‐documented hallmark of CRC phenotype. Accumulation of aberrant DNA methylation and histone acetylation orchestrates to modify gene activity and drive tumor onset, progression and metastasis. In this study we evaluated the effect of suberoylanilide hydroxamic acid (SAHA), a pan histone deacetylase inhibitor, and decitabine (DAC), a DNA methyltransferase inhibitor, either alone or in combination, on Caco‐2 human colon cancer cell line in vitro. Our results showed that SAHA and DAC, separately, significantly decreased cell proliferation, induced apoptosis and cell cycle arrest of Caco‐2 cell line. On the other hand, the sequential treatment of Caco‐2 cells, first with DAC and then with SAHA, induced a synergistic anti‐tumor effect; the sequential treatment significantly enhanced growth inhibition and apoptosis of Caco‐2 cell line in comparison to cells treated with either drug alone. Furthermore, the combination therapy upregulates protein expression levels of pro‐apoptotic proteins Bax, p53 and cytochrome c, down regulates the expression of anti‐apoptotic Bcl‐2 protein and increases the cleavage of procaspases 8 and 9; this suggests that the combination activates apoptosis via both the intrinsic and extrinsic pathways. Mechanistically, we demonstrated that the synergistic anti‐neoplastic activity of combined SAHA and DAC involves an effect on PI3K/AKT and Wnt/β‐catenin signaling pathways as it down regulates p‐PI3K, p‐AKT, Wnt1, p‐GSK3, cyclin A1+A2, cyclin E1 and up regulates p‐β‐catenin protein expression levels. In conclusion, our results provide evidence for the profound anti‐tumorigenic effect of sequentially combined SAHA and DAC in CRC cell line and offer new insights into the corresponding underlined molecular mechanism.Support or Funding InformationThis work was funded by SRDC, School of Arts and Sciences, Lebanese American UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.