Epigenetic Regulation of TRAIL Signaling: Implication for Cancer Therapy

Abstract

One of the main characteristics of carcinogenesis relies on genetic alterations in DNA and epigenetic changes in histone and non-histone proteins. At the chromatin level, gene expression is tightly controlled by DNA methyl transferases, histone acetyltransferases (HATs), histone deacetylases (HDACs), and acetyl-binding proteins. In particular, the expression level and function of several tumor suppressor genes, or oncogenes such as c-Myc, p53 or TRAIL, have been found to be regulated by acetylation. For example, HATs are a group of enzymes, which are responsible for the acetylation of histone proteins, resulting in chromatin relaxation and transcriptional activation, whereas HDACs by deacetylating histones lead to chromatin compaction and the subsequent transcriptional repression of tumor suppressor genes. Direct acetylation of suppressor genes or oncogenes can affect their stability or function. Histone deacetylase inhibitors (HDACi) have thus been developed as a promising therapeutic target in oncology. While these inhibitors display anticancer properties in preclinical models, and despite the fact that some of them have been approved by the FDA, HDACi still have limited therapeutic efficacy in clinical terms. Nonetheless, combined with a wide range of structurally and functionally diverse chemical compounds or immune therapies, HDACi have been reported to work in synergy to induce tumor regression. In this review, the role of HDACs in cancer etiology and recent advances in the development of HDACi will be presented and put into perspective as potential drugs synergizing with TRAIL’s pro-apoptotic potential.

Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL‐101 in Acute T Lymphocytic Leukemia

“…Many researches have reported that HDACi can induce G1 phase arrest with reduction of c-Myc and induction of p21 [30,[36][37][38]. It is clear that c-Myc expression levels tightly relate to cell proliferation.…”

Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP

“…While tumor necrosis factor-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis of tumor cells [ 9 , 11 , 49 , 50 ], approximately 20% of them develop resistance to TRAIL, limiting its potential use in clinic [ 22 , 49 , 51 ]. Surprisingly, cancer cells’ refractory to conventional chemotherapy, sometimes displays high sensitivity to TRAIL-induced cell death [ 52 , 53 , 54 ].…”

Curcumin—A Viable Agent for Better Bladder Cancer Treatment

“…c-myc is not only linked to survival, proliferation, and angiogenesis but is also involved in epigenetic control of EMT. Recent reports document a close cross-communication between c-myc and HDAC [82,83], which is highly relevant from a clinical viewpoint. Nearly 90% of all cancers are thought to be caused by epigenetic modification [84], whereby elevated expression of HDACs correlate with a poor prognosis [85].…”

“…Kamat et al [81] did not investigate the HDAC expression level and histone acetylation in their study. However, up-regulation of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors under curcumin treatment and BCG might be traced back to a c-myc-HDAC interaction [83]. Since curcumin has been identified as a natural HDAC-inhibitor, it may therefore carry high potential in supporting a BCG-based regimen.…”