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.

Keywords: TRAIL; cancer; chromatin remodeling; histone deacetylase (HDAC); histone deacetylase inhibitors (HDACIs); methylation; silencing; tumor necrosis factor (TNF).

Figure 1

Illustration of histone core composition and impact of chromatin relaxation or compaction by histone acetyltransferases (HAT) or histone deacetylases (HDAC) on gene expression (a) Histone protein consists of five main types H1, H2A, H2B, H3, and H4. Two copies of each histone type (2H2A, 2H2B, 2H3, and 2H4) constitute the octamer histone core (nucleosome), wrapped by approx. 146 bp of DNA. H1 is known as linker histone that is associated to linker DNA between each nucleosome. (b) Epigenetic modification of histone proteins by HDAC/HAT. HAT stimulates transcriptional activation of the tumor suppressor genes via acetylation of N-ε-lysine residues of histone results in more relaxed chromatin, which facilitates the accessibility of target gene promoter to transcription factors. Conversely, HDAC induces transcriptional repression of tumor suppressor genes by deacetylating N-ε-lysine residues of histone in which the chromatin adopts compacted structure conformation, thus hiding the target gene promoter from the transcription factors.

Figure 2

Different classes of HDACs. Four different classes of HDACs were identified in mammalian cell based on their sequence homology and structure similarity to the corresponding yeast HDACs. Class I is homologous to the yeast reduced potassium dependency 3 (RPD3) and includes HDAC1, 2, 3, 8. Class II is homologous to yeast Hda1 and divided into two sub classes, class IIa HDAC4, 5, 7, 9 and class IIb HDAC6, 10. Class III is also known as sirtuins that contain SIRT1-7. Class IV has its own character and shows structural similarity to classes I and II.

Figure 3

Different HAT/KAT subtypes and their domains. Besides the lysine acetyltransferase domain, KAT can harbor a bromodomain that can facilitate interactions with modified histones. The MYST and CBP families also contain a zinc-binding domain which facilitates DNA binding. Some MYST family HATs contain in addition an N-terminal chromodomain, which binds to methylated lysine residues. HAT = catalytic histone acetyltransferase domain, BRO = bromodomain, CHR = chromodomain, ZN = zinc-binding domain.

Figure 4

Illustrating the physiological function of HDAC. HDAC can be recruited to gene promoter associated with coregulatory proteins including (a) methyl binding protein (MeCP2), (b) DNA methyl transferases (DMNT), Estrogen receptor (ER), and transcription factors Rb and E2F, which are responsible for gene silencing and subsequent chromatin remodeling [37].

Figure 5

Recruitment of HDAC to retinoic acid-responsive elements (RARE) in Promyelocytic leukemia (PML). HDAC forms a multiprotein complex with RAR-PLZF, resulting in the transcriptional repression of retinoic acid receptor (RAR) target gene, responsible for normal differentiation and proliferation of myeloid cells. HDACi can reverse this case by restoring the sensitivity of PML to retinoic acids.

Figure 6

Schematic representation of the molecular mechanism of HDCAIs-induced cell cycle arrest and induction of apoptotic cell death. P21 gene promoter Sp1 can bind HDAC multi protein complex repressing gene transcription. Inhibition of HDAC activates transcription of p21 that stimulates cell cycle arrest. HDACIs can also induce apoptosis via stimulation of tumor necrosis factor (TNF) protein members like TRAIL and CD95.

Figure 7

Structure of selected HDAC inhibitors. FDA approved inhibitors are highlighted in the grey boxes.

Figure 8

Schematic representation of the main molecular events-induced by HDAC inhibitors preventing tumor metastasis and inducing tumor cell death.

Figure 9

Schematic diagram summarizing the different cell death signaling pathways-induced by epigenetic modification of chromatin following treatment with HDAC inhibitors and demethylating agents.

Figure 10

(a) Epigenetic regulation of survivin in transformed cells. The promoter region of survivin is hypermehylated thus inhibiting TRAIL-dependent apoptotic signaling pathway. In contrast, hypomethylation of survivin promoter facilitates the binding of p53 repressing its transcriptional activation. (b) Epigenetic alterations represented in the methylation of TRAIL death receptors (DR4, DR5, DcR1, and DcR2) confer significant contributions to TRAIL-resistance in different type of tumors. Several DNA (Dmnt1&Dmnt3) and histone (KDM2B&KDM4A) methylases control the regulation of these receptors on the genomic level. Demethylation drugs such as azacitidine and decitabine as well as HDACIs like SAHA, TSA, and sodium butyrate can restore TRAIL sensitization.

Figure 11

Schematic representation of epigenetic events regulating TRAIL-induced apoptosis. (a) Main genes regulated by HDACi, either positively or negatively. (b) Illustration of the main epigenetic events affecting chromatin compaction and inhibitors that stimulate chromatin relaxation-based histone acetylation. Bromo-and extra terminal domains (BET) specifically bind to acetylated histones, regulating either positively or negatively genes in the neighborhood. Methylation of CpG island by DNA methylases also contribute to gene silencing. (c) HDACi can also regulate gene expression and increase sensitivity to TRAIL-induced apoptosis through acetylation of non-histone proteins. Acetylation of c-Myc induce its degradation whereas acetylation of Ku70 and p53, on the other hand, lead to enhanced TRAIL-induced cell death due to degradation of c-FLIP and upregulation of pro-apoptotic gene expression. HDACi can also induce regulation of TRAIL death receptors (DR4 & DR5) gene expression through the ER-stress sensors ATF4 and CHOP, see text.