The role of ubiquitination in tumorigenesis and targeted drug discovery

Abstract

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.

Fig. 1

The components and processes of the UPS. a The components of the UPS and different classes of E3 ligases. b The ubiquitination linkage

Fig. 2

Ubiquitination in tumor metabolism regulation. a Ubiquitination in the mTORC1 signaling pathway. b Ubiquitination in the PTEN-AKT signaling pathway. c Ubiquitination of key transcription factors in cell metabolism regulation

Fig. 3

Ubiquitination in immunological tumor microenvironment (TME) modulation. a Ubiquitination in the TLR signaling pathway. b Ubiquitination in the RLR signaling pathway. c Ubiquitination in the STING-dependent signaling pathway

Fig. 4

Ubiquitination in cancer stem cell (CSC) stemness maintenance. a The ubiquitination-mediated regulation of the transcriptional regulatory network in maintaining the stemness of stem cells. b Ubiquitination in the Wnt and HIPPO signaling pathways

Fig. 5

Cancer therapeutic strategy by targeting the UPS