Ubiquitin Pathway and Ovarian Cancer

Abstract

E1 binds to ubiquitin, activates it in an atpdependent process by thioester bond, and then passes it to E2. Ubiquitin is then transferred by E2 to a lysine residue in the substrate by terminal isopeptide bond through E3, a scaffold protein. E3 makes a ligation between the substrate and the ubiquitin-linked E2. The resulting covalent ubiquitin ligations form polyubiquitinated conjugates that are detected and rapidly degraded by the 26S proteasome. Polyubiquitin chains also serve as a signal for proteasome-dependent degradation; monoubiquitination is a signal for endocytosis or subnuclear trafficking. K63-linked polyubiquitin chains signal endocytosis, ikk activation, ribosome modification, or dna repair. The E3 enzyme provides the substrate specificity in all of those processes. In this way, there is a specific E3 for each substrate 3 . Thus, the ubiquitin-proteasome pathway plays a critical role in the degradation of several proteins involved in the cell cycle. Dysregulation of this pathway leads to inhibition of cellular proliferation and the induction of apoptosis 4 . Ubiquitination and its downstream consequences have therefore been investigated intensively as targets for the development of drugs for tumour therapy.Ovarian cancer is a neoplastic growth arising from various parts of the ovary, mainly the outer lining and the fallopian tube. Ovarian cancer is the fifth leading cause of death from cancer in women and the leading cause of gynecologic cancer death 5 . In this review article, we discuss the involvement of the ubiquitin pathway in the progress of ovarian cancer and possible targeting for ovarian cancer treatment.

Ubiquitin—Proteasome Axis, Especially Ubiquitin-Specific Protease-17 (USP17) Gene Family, is a Potential Target for Epithelial—Mesenchymal Transition in High-Grade Serous Ovarian Cancer

“…40 Similarly, Rao et al mentioned in a review that ubiquitination might interfere with ERK, CDK, and p53 pathways and ERBB2 gene expression in ovarian cancer. 41 A relevant study with our research is the Wang et al's study regarding USP14 and ovarian cancer. They found USP14 enzyme level significantly higher in patients with ovarian cancer compared to controls.…”

“…40 Similarly, Rao et al mentioned in a review that ubiquitination might interfere with ERK , CDK, and p53 pathways and ERBB2 gene expression in ovarian cancer. 41…”

Evaluating Ovarian Cancer Chemotherapy Response Using Gene Expression Data and Machine Learning

“…The ubiquitin-proteasome pathway plays an important role in the regulation of cellular proteins involving cell cycle control, transcription, apoptosis, cell adhesion, angiogenesis, and tumor growth [96]. Various ways that the ubiquitin pathway is involved in OC, such as modulating the ovarian-cancer-related gene BRCA1 and tumor suppressor p53, and interfering with the ERK pathway, the cyclin-dependent cell cycle regulation process, and ERBB2 gene expression [96]. HSPA2, one of stress-non-inducible and least characterized members of the HSPA family (HSP70), is ubiquitous in various types of cancer cells [97].…”

Integrated bioinformatics analysis of validated and circulating miRNAs in ovarian cancer

“…Firstly, ubiquitin-mediated proteolysis is an essential mechanism that is responsible for 80%–90% of intracellular protein degradation and is involved in many cellular processes, including tumorigenesis, tumor survival and apoptosis [ 22 , 23 ]. Ubiquitin-mediated pathway modulates BRCA1/2 , p53, ERBB2 gene expressions, ERK pathway, cyclin-dependent cell cycle regulation which are related to OC [ 24 ]. Bazzaro et al [ 25 ] claimed that upregulation of proteasome subunit levels occurs in OC and proteasome inhibitors may have utility in the treatment of OC.…”