Am J Clin Exp Immunol 2013;2(1):55-74

Review Article
Epigenetic regulation of the TRAIL/Apo2L apoptotic pathway by his-tone
deacetylase inhibitors: an attractive approach to bypass mela-noma
immunotherapy resistance

Ali R Jazirehi, Dylan Arle

Department of Surgery, Division of Surgical Oncology, and the Jonsson Comprehensive Cancer Center, David Geffen
School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California 90095

Received December 26, 2012; Accepted January 19, 2013; Epub February 27, 2013; Published March 9, 2013

Abstract: TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) is a major cytotoxic mechanism employed by cytotoxic T
lymphocytes (CTL) and natural killer (NK) cells to eradicate malignant cells. TRAIL/Apo2L interacts with its cognate
receptors located on tumor cell surface namely, TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1), TRAIL-R4 (DcR2)
and osteoprotegerin (OPG). The exact function of DcR1 and DcR2 remains elusive. TRAIL/Apo2L or agonistic
monoclonal antibodies directed against TRAIL/Apo2L death-inducing receptors (DR4, DR5) have become an attractive
immunological therapeutic tools in clinical oncology due to their selective killing of tumors and lack of affinity towards
healthy cells. Though a potent anti-cancer modality, some cancer cells exhibit inherent or acquired resistance to
TRAIL/Apo2L. Postulated resistance mechanisms include up-regulation of c-FLIP, down -regulation of caspase-8,
down-regulation/shedding of death receptors and an imbalanced ratio of pro- to anti-apoptotic genes due to aberrant
activity of cellular survival signal transduction pathways. The development of resistance has spurred the use of
combination therapy, in particular using small molecule sensitizing agents, to restore apoptosis sensitivity. A novel
category of such compounds is histone deacetylase inhibitors (HDACi), which block HDACs from removing acetyl
groups from histone tails thereby preventing silencing of pro-apoptotic genes and regulating the expression of
non-histone proteins (i.e., apoptosis-associated genes), are effective agents in some malignancies. Some HDACi, such
as Suberoylanilide Hydroxamic Acid (SAHA), have received FDA approval for cancer treatment. In various melanoma
preclinical models, HDACi in conjunction with TRAIL/Apo2L, via modulation of apoptotic machinery, have proven to
overcome acquired/inherent resistance to either agent. Here, we discuss recent findings on the role of TRAIL/Apo2L and
its agonistic mAbs in melanoma immunotherapy with discussions on potential cellular and molecular events by which
HDACi can sensitize metastatic melanoma to TRAIL/Apo2L-mediated immune-therapy, thereby, overcoming resistance.

Keywords: TRAIL/Apop2L, apoptosis, signal transduction, resistance, melanoma, immunotherapy, SAHA, histone
deacetylase inhibitor, sensi-tization, adoptive cell transfer, agonistic TRAIL/Apo2L mAbs, monoclonal antibody,
drozitumab, gene regulation

Address correspondence to: Dr. Ali Jazirehi, CLS, Division of Surgical Oncology, CHS 54-140, University of California,
Los Angeles, 10833 LeConte Avenue, Mail code: 178218, Los Angeles, CA 90095. Phone: 310-206-8509; Fax:
310-267-2679; E-mail:
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