Regulation of apoptosis by ubiquitination in liver cancer

Abstract

Apoptosis is a programmed cell death process critical to cell development and tissue homeostasis in multicellular organisms. Defective apoptosis is a crucial step in the malignant transformation of cells, including hepatocellular carcinoma (HCC), where the apoptosis rate is higher than in normal liver tissues. Ubiquitination, a post-translational modification process, plays a precise role in regulating the formation and function of different death-signaling complexes, including those involved in apoptosis. Aberrant expression of E3 ubiquitin ligases (E3s) in liver cancer (LC), such as cellular inhibitors of apoptosis proteins (cIAPs), X chromosome-linked IAP (XIAP), and linear ubiquitin chain assembly complex (LUBAC), can contribute to HCC development by promoting cell survival and inhibiting apoptosis. Therefore, the review introduces the main apoptosis pathways and the regulation of proteins in these pathways by E3s and deubiquitinating enzymes (DUBs). It summarizes the abnormal expression of these regulators in HCC and their effects on cancer inhibition or promotion. Understanding the role of ubiquitination in apoptosis and LC can provide insights into potential targets for therapeutic intervention.

Keywords: Apoptosis; E3s; hepatocellular carcinoma; ubiquitin.

Figure 1

Overview of ubiquitin-mediated regulation of TNFR1-induced apoptosis. When trimer TNF-α binds to trimer TNFR1, Complex I is formed through interprotein and Ub chain-mediated interactions. Complex I is formed before Complex II and mainly activates the MAPKs and NF-κB pathways to produce inflammatory cytokines and antiapoptotic proteins. If RIPK1 or others major component is not ubiquitinated, they can dissociate from complex I and form complex IIa or IIb. Complex IIa (RIPK1/FADD/TRADD) and IIb (RIPK1/RIPK3/MLKL) mediate apoptosis and necroptosis, respectively. The TNFR1 signaling pathway is finely regulated by E3s and DUBs, and these regulators are abnormally expressed in LC (see Table 1 for details).

Figure 2

Overview of ubiquitin-mediated regulation of TRAIL-R-induced apoptosis. When trimer TRAIL binds to trimer TRAIL-R, Complex I is formed through interprotein and Ub chain-mediated interactions. The TRAIL signaling pathway is finely regulated by E3s and DUBs, and these regulators are abnormally expressed in LC (see Table 2 for details).

Figure 3

Overview of ubiquitin-mediated regulation of intrinsic apoptosis. The core of intrinsic apoptosis is the change of Mitochondrial Outer Membrane Permeabilization (MOMP) mediated by Bax/Bak. Upon MOMP, some cytokines like SMAC, AIF, Omi, and ARTS were released into the cytoplasm causing activation of caspases and sequent apoptosis. The activity of Bax/Bak is largely regulated by the proapoptotic BH3-only protein and the antiapoptotic Bcl-2 proteins. E3s and DUBs finely regulate the processes; these regulators are abnormally expressed in LC (see Table 3 for details). Under certain conditions, such as phosphorylation and ER stress, the binding ability of E3s and DUBs to substrates is affected.