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Review
. 2022 Oct 30;14(21):5354.
doi: 10.3390/cancers14215354.

The E3 Ligases in Cervical Cancer and Endometrial Cancer

Fengguang Zhai  1   2 , Jie Wang  1   2 , Weili Yang  3 , Meng Ye  1   2 , Xiaofeng Jin  1   2
Affiliations
Review

The E3 Ligases in Cervical Cancer and Endometrial Cancer

Fengguang Zhai et al. Cancers (Basel). .

Abstract

Endometrial (EC) and cervical (CC) cancers are the most prevalent malignancies of the female reproductive system. There is a global trend towards increasing incidence and mortality, with a decreasing age trend. E3 ligases label substrates with ubiquitin to regulate their activity and stability and are involved in various cellular functions. Studies have confirmed abnormal expression or mutations of E3 ligases in EC and CC, indicating their vital roles in the occurrence and progression of EC and CC. This paper provides an overview of the E3 ligases implicated in EC and CC and discusses their underlying mechanism. In addition, this review provides research advances in the target of ubiquitination processes in EC and CC.

Keywords: E3 ligase; cervical cancer; endometrial carcinoma; targeted therapies.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1
Figure 1
Ubiquitination processes. Substrate ubiquitination is an ordered process. First, under the premise of ATP energy supply, the Ub molecule is activated by E1, and the 76th Gly at the Ub terminus forms a mercaptan lipid bond with E1 cysteine. Subsequently, Ub is shifted to E2 by the E1 intermediate. Finally, E3 ligase transfers Ub directly or indirectly to substrates by recruiting E2. The substrate binds to lysine residues of the Ub polypeptide to form seven poly-Ub chains with different fates: K11 and K48 are commonly associated with substrate degradation. K6, K63, K27, K29, and K33 mediate the regulation of various substrate functions. For example, DNA damage repair, protein autophagy, lysosomal degradation, signal transduction, and so on. M1 and linear Ub chain can positively regulate the nuclear factor kappa-B (NF-κB) signaling.
Figure 2
Figure 2
The role of E3 ligases in the p53 pathway, the Nuclear Factor Kappa-B (NF-κB) pathway, the EGFR pathway, the Wnt/β-catenin pathway, the TGF-β/Smad pathway in endometrial carcinoma (EC) and cervical cancer (CC). The p53 signaling pathway: E3 ligases murine double minute 2(MDM2), E6AP, and TRIM65 directly bind to p53 and promote ubiquitination degradation of p53. p53 protein, in turn, induces MDM2 to regulate itself through self-ubiquitination. Furthermore, RBBP6 promotes the phosphorylation of c-Jun NH2-terminal kinase (JNK) to regulate the expression of p53. In CC cells, FHL2 binds to IER3 and MDM2 to form a ternary complex that allows for efficient MDM2-mediated degradation of IER3 by enhancing the association between MDM2 and IER3. NF-κB pathway: E3 ligase TRIM22 directly binds to nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Reducing the phosphorylation of p65 and IκBα reduces NF-κB signal transduction. Epidermal growth factor receptor (EGFR) pathway: makorin RING finger protein 1 (MKRN1) can be phosphorylated by the EGFR/PI3K/AKT pathway to continuously degrade PTEN protein in a K48-dependent manner. Wnt/β-catenin pathway: RNF43 directly interacts with Wnt and promotes its degradation, thereby inhibiting continuous activation of the Wnt/β-catenin pathway. TGF-β/Smad pathway: Activated TGF-β ligand interacts with two transmembrane receptors TβRI and TβRII, to form a tetrameric complex. Constitutively activated TβRII phosphorylates and activates TβRI, which directly phosphorylates downstream transcription factors Smad 2 and Smad 3 through its serine/threonine kinase activity. Activated Smad2 or Smad3 can bind to Smad4, migrate to the nucleus, and bind to different TFs to achieve excessive activator or suppressor activity. SCFSkp2/Cks1 directly interacts with p27 and ubiquitinate it.
Figure 3
Figure 3
PROTAC-mediated degradation of target proteins through the ubiquitin–proteasome system (UPS). Selective androgen receptor modulator (SARM) and nutlin assemble into a complex that hijacks murine double minute 2 (MDM2). SARM with nutlin binds MDM2 and intracellular androgen receptor (AR), labels AR with ubiquitin, and then induces cells to remove AR by proteasomes.
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