New Insights into the Epigenetics of Hepatocellular Carcinoma

Figure 2

Emerging signaling pathways in HCC: chromatin remodeling: restricting transcriptional and DNA condensation occurs as a result of histone deacetylation catalyzed by HDACs in nucleosome. In contrast, transcriptional activation also occurs using chromatin remodeling complexes by allowing access to transcription machinery via nucleosome restructuring. Notch signaling: NOTCH receptor is cleaved photolytically when protein ligand binds to its extracellular domain. This binding releases its intracellular domain (NOTCH-ICD) that enters into nucleus to modify target gene expression (such as SOX9, HEY, and HES). Hedgehog (Hh) signaling: nuclear translocation of the transcription factor (TF) GLI occurs as a result of PTCH inhibitory effect on SMO and this event takes place in the presence of Hh signaling. Hippo signaling: kinase complexes Lats1/2-Mob1 and MST1/2-SVA1 are activated with phosphorylation of the transcription factor YAP resulting in prevention of its nuclear translocation. This event involves the use of upstream regulators of hippo pathway (i.e., FDM6, NF2, and FAT). Microbiota and lymphotoxins: NF-kβ signaling activates and produces proinflammatory molecules such as TNF-α and cytokines due to recognition of microbial ligands (LPS/PAMPs) by TLKRs (e.g., TLK4) on the hepatic stellate cells [126].