The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer

Abstract

Ubiquitination, a highly adaptable post-translational modification, plays a pivotal role in maintaining cellular protein homeostasis, encompassing cancer chemoresistance-associated proteins. Recent findings have indicated a potential correlation between perturbations in the ubiquitination process and the emergence of drug resistance in CRC cancer. Consequently, numerous studies have spurred the advancement of compounds specifically designed to target ubiquitinates, offering promising prospects for cancer therapy. In this review, we highlight the role of ubiquitination enzymes associated with chemoresistance to chemotherapy via the Wnt/β-catenin signaling pathway, epithelial-mesenchymal transition (EMT), and cell cycle perturbation. In addition, we summarize the application and role of small compounds that target ubiquitination enzymes for CRC treatment, along with the significance of targeting ubiquitination enzymes as potential cancer therapies.

Keywords: CRC; Chemoresistance; Targeted therapy; Ubiquitination enzymes.

Fig. 1

The flowchart illustrates the contents of the present review. A Ubiquitination process involves Ub, E1, E2, and E3 ubiquitin ligases. ATP activates the E1 enzyme and binds to Ub. The Ub-E1 intermediate then transfers the activated Ub to the E2 enzyme. Finally, Ub is transferred to a specific substrate by E3 ubiquitin ligases, which are categorized as the really interesting new gene (RING)-type E3 ligases, the U-box-type E3 ligases, the HECT-type E3 ligases, or the RBR-type E3 ligases. In RING and U-box E3 ubiquitin ligases, the Ub is transferred directly from the E2 enzyme to the substrate. HECT E3 ligase transfers Ub to the C lobe of HECT, and then Ub is transferred back to the substrate. RBR E3 ubiquitin ligase transfers Ub through the two RING domains. Subsequently, the substrate with the Ub linkage is destined for degradation or to participate in DNA repair, kinase activation, transcriptional regulation, and growth reactions. B, C ubiquitination enzymes are involved in the process of resistance to first-line chemotherapeutic agents, such as 5-FU, CPT-11, L-OHP, and Cetuximab, mainly through their involvement in the Wnt/β-catenin signaling pathway, EMT, cell cycle perturbation, and others. D Various small-molecule drugs that target ubiquitination enzymes are being developed for use in the clinical management of CRC

Fig. 2

The role of ubiquitination enzymes in the Wnt/β-catenin signaling pathway of CRC. Under normal cellular conditions (in the absence of WNT), β-catenin in the cytoplasm undergo UPS-mediated degradation by interacting with a destructive complex (DC) consisting of APC, Axin, CK1 and glycogen synthase kinase 3 (GSK3-β). DVL removes FZD₆ from the cell membrane via RNF43/ZNRF3 binding. LPR is also deleted. The ubiquitination enzymes β-TrCP and UBES2S promote the degradation of β-catenin. On the other hand, Wnt binding to the LPR and FZD₆ prevents β-catenin degradation, the C-terminus of LRP is phosphorylated and the binding of Axin inhibits the interaction of β-catenin with DCs, leading to stable transfer of β-catenin to the nucleus that binds to the TCF/LEF transcription factors to activate transcription of Wnt target genes. Expression of β-catenin is promoted by TRIM29 and TRIM27. RNF14 promotes β-catenin binding to TCF/LEF. β-Catenin degradation has been shown to be inhibited by NEDD4L, Smurf2, CRBN, SIAH and RNF146

Fig. 3

Cell cycle regulation of ubiquitination enzymes in CRC. The stages of the cell cycle are divided into four major phases: (1) G1 phase. (2) S phase. (3) G2 phase. (4) M phase. CHFR promotes G2/ -stage cell cycle arrest. c-Myc also promotes cell cycle arrest in G2/M phase and S phase. APC/C^CDC20 regulates cell cycle progression through the M and S phase. Furthermore, SKP2 promotes cell cycle arrest at the G1/S transition. TRIM72 promotes G1-phase cell cycle arrest. Cyclin F inhibits the activity of transcription motors in the G2 cell cycle. RFPL4A has been shown to induce G1 arrest in CRC cells