Role of Ubiquitination and Epigenetics in the Regulation of AhR Signaling in Carcinogenesis and Metastasis: "Albatross around the Neck" or "Blessing in Disguise"

Abstract

The molecular mechanisms and signal transduction cascades evoked by the activation of aryl hydrocarbon receptor (AhR) are becoming increasingly understandable. AhR is a ligand-activated transcriptional factor that integrates environmental, dietary and metabolic cues for the pleiotropic regulation of a wide variety of mechanisms. AhR mediates transcriptional programming in a ligand-specific, context-specific and cell-type-specific manner. Pioneering cutting-edge research works have provided fascinating new insights into the mechanistic role of AhR-driven downstream signaling in a wide variety of cancers. AhR ligands derived from food, environmental contaminants and intestinal microbiota strategically activated AhR signaling and regulated multiple stages of cancer. Although AhR has classically been viewed and characterized as a ligand-regulated transcriptional factor, its role as a ubiquitin ligase is fascinating. Accordingly, recent evidence has paradigmatically shifted our understanding and urged researchers to drill down deep into these novel and clinically valuable facets of AhR biology. Our rapidly increasing realization related to AhR-mediated regulation of the ubiquitination and proteasomal degradation of different proteins has started to scratch the surface of intriguing mechanisms. Furthermore, AhR and epigenome dynamics have shown previously unprecedented complexity during multiple stages of cancer progression. AhR not only transcriptionally regulated epigenetic-associated molecules, but also worked with epigenetic-modifying enzymes during cancer progression. In this review, we have summarized the findings obtained not only from cell-culture studies, but also from animal models. Different clinical trials are currently being conducted using AhR inhibitors and PD-1 inhibitors (Pembrolizumab and nivolumab), which confirm the linchpin role of AhR-related mechanistic details in cancer progression. Therefore, further studies are required to develop a better comprehension of the many-sided and "diametrically opposed" roles of AhR in the regulation of carcinogenesis and metastatic spread of cancer cells to the secondary organs.

Keywords: apoptosis; cancer; preclinical trials; signaling; xenografted mice.

Figure 1

In the inactive state, AhR is primarily located in the cytoplasm and exists as a multi-protein complex with two chaperone proteins, HSP90 (heat shock protein 90) and co-chaperone p23. Moreover, AIP (AhR interacting protein) is a conserved co-chaperone protein that binds to many proteins, including AhR and HSP90. AhR ligands cross the plasma membrane and bind to AhR. These interactions allow the transportation of ligand-receptor complexes into the nucleus. ARNT (AhR nuclear translocator) is a basic Helix-Loop-Helix Motif containing transcriptional factor. Therefore, after accumulation of AhR in the nucleus, AhR forms heterodimers with its partner ARNT. Functionally active heterodimers bind specific DNA regions located in the promoter regions of different genes. AhR works with wide variety of co-factors and chromatin remodeling machinery. The steroid receptor co-activator (SRC) family of p160 proteins consists of SRC-1 (NcoA-1), SRC-2 and SRC-3. AhR/ARNT complex promoted the recruitment of SRC family of transcriptional co-activators. Histone deacetylases (HDACs) are displaced by AhR and histone acetyltransferases are recruited by AhR to stimulate transcriptional gene networks.

Figure 2

AhR stimulated transcriptional activation of ADAM10. ADAM10-specific inhibitors efficiently reduced the shedding of NKG2DL and enhanced its binding to NKG2D receptors. STAT proteins directly bind to the promoter regions of NK receptors (NKG2D and NKp46). Treatment with STAT inhibitors resulted in a decline in the expression of NKG2D and NKp46.

Figure 3

IDO1 and TDO2 catalyze the production of kynurenine. Oncogenic AhR transcriptionally upregulates different oncogenic networks. Calpain-10 has the ability to proteolytically cleave AhR and block AhR-mediated signaling. TDO overexpression promotes metastasis, but inhibition of TDO abolishes metastatic spread.

Figure 4

(A,B) USP14 deubiquitinated IDO1 and enhanced its stability. However, TRIM21 enhanced ubiquitination and degraded IDO1. IDO1 stability caused an increase in the production of kynurenine and activated AhR. Therefore, USP14 promoted tumorigenesis and promoted the mobilization of regulatory CD25+FOXP3+ CD4+ T cells and impaired the immunological response of killer T cells. However, inhibition of IDO1 potentiated the accumulation of Granzyme B+ CD8+ T cells and reduced tumorigenesis. (C) AhR transcriptionally regulates different ubiquitin ligases. AhR inactivated RNF182 but enhanced the expression of UBE2L3. (D) UBE2L3 has dualistic roles. It not only ubiquitinated and degraded HPV-encoded oncogenic proteins but also tagged tumor suppressor proteins like p53 for degradation. (E) UCHL3-mediated cancer promoting effects are inhibited by miRNA-582-5p. However, LINC00665 promoted the expression of UCHL3 and potentiated the deubiquitination of AhR. Stable AhR triggered the expression of oncogenic networks. (F) AhR stimulated CHIP/STUB1 and inhibited metastasis. (G) YL-109 impaired metastatic colonization of MDA-MB-231 cancer cells to the lungs of experimental mice.

Figure 5

(A) Multi-protein complex consisting of NR2E3, SP1 and GRIP1 stimulates the expression of AhR. However, NR2E3 loss promoted the recruitment of LSD1 (Lysine-specific histone demethylase-1). Thus, LSD1 reduces the levels of H3K4me2 and transcriptionally represses AhR. (B) AhR transcriptionally upregulated MALAT1. MALAT1 worked synchronously with EZH2 and increased the levels of H3K27me3. (C) AhR transcriptionally stimulates the expression of SUV39H1. Resultantly, SUV39H1 transcriptionally represses SOCS3 by increasing the levels of H3K9me2.