INHIBITION OF AN EPIGENETIC MODULATOR, HISTONE DEACETYLASE BY PEITC IN BREAST CANCER – A DETAILED MECHANISTIC APPROACH


MADHUMITA ROY, SUTAPA MUKHERJEE, JAYDIP BISWAS

ABSTRACT
Histone deacetylases (HDACs) are enzymes that modify the architecture of chromatin leading to decreased gene expression, the effect of which may be reversed by HDAC inhibition. The balance between acetylation and deacetylation of histones play a key role in many biological events including regulation of cell proliferation and cancer. There are certain inhibitors of HDACs which showed toxicity, therefore search of natural inhibitors is of tremendous importance. The aim of the present study is to investigate the effect of PEITC, a natural isothiocyanate found in cruciferous vegetables on HDAC and to elucidate the mechanism of action. We found that PEITC significantly inhibited the expression of class I HDACs (HDAC1 and HDAC2), both at protein and genetic level in two different human breast cancer cell lines: breast adenocarcinoma cell MCF-7, having wild type p53 and metastatic breast cancer cell MDA-MB-231, having mutated p53. Inhibition of HDAC 1 and 2 were associated with increased acetylation of lysine residues of histones H3 and H4. p53 and cMyc expressions are expected to play a role in regulation of telomerase activity. PEITC furthermore markedly inhibited the activity of telomerase and the expression of human telomerase reverse transcriptase (hTERT), which is the main determinant of the telomerase enzymatic activity. Transcriptional downregulation of hTERT mRNA by PEITC is mediated by repression of transcription factor c-Myc in both the cell lines. PEITC induced upregulation of p21 and p27 proteins independent of p53 status and this may be due to the downregulation of c-Myc expression. Elevated expressions of p21 and p27 were associated with concommitant downregulation of cyclin D level, a cell cycle regulatory protein, which is a probable cause of cell cycle arrest. PEITC therefore may be a potential compound that can be used as an antitumor agent in breast cancer irrespective of p53 status.