E2 ubiquitin-conjugating enzymes in cancer: Implications for immunotherapeutic interventions

Despite the medical advances of the 21st century, the incidence of cancer continues to increase and the search for a universal cure remains a major health challenge. Our lack of understanding the complex pathophysiology of the tumor microenvironment has hindered the development and efficiency of anti-cancer therapeutic strategies. The tumor microenvironment, composed of multiple cellular and non-cellular components, enables tumor-promoting processes such as proliferation, angiogenesis, migration and invasion, metastasis, and drug resistance. The ubiquitin-mediated degradation system is involved in several physiologic processes including cell cycling, signal transduction, receptor downregulation, endocytosis and transcriptional regulation. Ubiquitination includes attachment of ubiquitin to target proteins via E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. Several studies have shown that E2 enzymes are dysregulated in variety of cancers. Multiple investigations have demonstrated the involvement of E2s in various tumor-promoting processes including DNA repair, cell cycle progression, apoptosis and oncogenic signaling. E2 enzymes consist of 40 members that facilitate ubiquitin-substrate conjugation thereby modulating the stability and interaction of various proteins. As such, E2s are potential biomarkers as diagnostic, prognostic and therapeutic tools. In this review, we discuss the role of E2s in modulating various types of cancer.