Targeting Epigenetics in Cancer

Abstract

Alterations of genes regulating epigenetic processes are frequently found as cancer drivers and may cause widespread alterations of DNA methylation, histone modification patterns, or chromatin structure that disrupt normal patterns of gene expression. Because of the inherent reversibility of epigenetic changes, inhibitors targeting these processes are promising anticancer strategies. Small molecules targeting epigenetic regulators have been developed recently, and clinical trials of these agents are under way for hematologic malignancies and solid tumors. In this review, we describe how the writers, readers, and erasers of epigenetic marks are dysregulated in cancer and summarize the development of therapies targeting these mechanisms.

Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21CIP1 in human breast cancer cell lines

“…The positive association between altered or overexpressed PRMT5, EZH2, or KDACs and onset of cancer has prompted scientists to explore modulators of these enzymes that have the potential to be used as epigenetic therapeutics . Very recently, we have observed the similar modulatory action of another well‐studied natural molecule—curcumin, which reduced expression and function of PRMT5/MEP50 in vitro .…”

“…Altered function or overexpression of PRMT5, EZH2, and KDACs is associated with many cancers . Increasing quest for inhibitors of both PRMT5 and EZH2 in recent research as well as clinical trials indicates the immense possibilities of their therapeutic targeting in cancer …”

“…6,9,10 Increasing quest for inhibitors of both PRMT5 and EZH2 in recent research as well as clinical trials indicates the immense possibilities of their therapeutic targeting in cancer. 6,[11][12][13] Resveratrol (RVT) a natural polyphenolic compound found in grapes and berries has been widely studied and is considered as an anti-cancer, anti-diabetes, cardioprotective, and antiinflammatory molecule. 14 Its molecular targets include AKT, mTOR, NF-kB, STAT, MAPK, AURKA, and PLK1, resulting in their inactivation and subsequent inhibition of cell proliferation.…”

Sp1‐mediated epigenetic dysregulation dictates HDAC inhibitor susceptibility of HER2‐overexpressing breast cancer

“…In addition, HER2‐positive breast cancer is characterized by eminent changes in the epigenome including histone modifications . However, it remains a matter of debate how these modifications occur on specific loci and how they are dynamically and reversibly regulated in breast cancer . In addition, HER2‐positive breast cancer has been successfully targeted by monoclonal antibodies and a class of tyrosine kinase inhibitors (TKIs) as exemplified by lapatinib, which have remarkably improved the outcome of patients .…”

Anticancer potential of naturally occurring immunoepigenetic modulators: A promising avenue?

“…Although dozens of synthetic and natural compounds have been described in preclinical and clinical trials, currently, there are only 6 US Food and Drug Administration (FDA)‐approved epigenetic drugs (Supporting Table 1). Two DNA hypomethylating DNMT inhibitors gained approval in 2004 and 2006, respectively, for the treatment of myelodysplastic syndromes: 5‐azacytidine (azacytidine; Vidaza; Celgene Corporation, Summit, NJ) and 5‐aza‐2′‐deoxycytidine (decitabine [DAC]; Dacogen; MGI Pharma, Inc, Woodcliff Lake, NJ). In addition, there are 4 HDAC inhibitor (HDACi) drugs: suberoylanilide hydroxamic acid (SAHA) (vorinostat; Zolinza; Merck & Company Inc, Whitehouse Station, NJ) and FK228 (romidepsin; Istodax; Celgene Corporation) were approved in 2006 and 2009, respectively, for the treatment of cutaneous T‐cell lymphoma; PXD101 (belinostat; Beleodaq; Spectrum Pharmaceuticals, Inc, Henderson, NV) gained approval in 2014 for the treatment of patients with relapsed or refractory peripheral T‐cell lymphoma; and LBH589 (panobinostat; Farydak; Novartis, Basel, Switzerland) was approved in 2015 for patients with multiple myeloma.…”