Otubain 1: a non-canonical deubiquitinase with an emerging role in cancer

Abstract

The ubiquitin system regulates diverse biological processes, many involved in cancer pathogenesis, by altering the ubiquitination state of protein substrates. This is accomplished by ubiquitin ligases and deubiquitinases (DUBs), which respectively add or remove ubiquitin from substrates to alter their stability, activity, localization, and interactions. While lack of catalytic activity makes therapeutic targeting of ubiquitin ligases difficult, DUB inhibitors represent an active area of research and the identification of cancer-associated DUBs may lead to the development of novel therapeutics. A growing body of literature demonstrates that the DUB Otubain 1 (OTUB1) regulates many cancer-associated signaling pathways including MAPK, ERa, EMT, RHOa, mTORC1, FOXM1 and P53 to promote tumor cell survival, proliferation, invasiveness, and therapeutic resistance. In addition, clinical studies have associated elevated OTUB1 expression with high grade, invasiveness, and metastasis in several tumor types including lung, breast, ovarian, glioma, colon, and gastric. Interestingly, in addition to catalytic DUB activity, OTUB1 displays a catalytic-independent, non-canonical activity where it inhibits the transfer of ubiquitin onto protein substrates by sequestration of E2 ubiquitin conjugating enzymes. The aim of this review is to describe the canonical and non-canonical activities of OTUB1, summarize roles for OTUB1 in cancer-associated pathways, and discuss its potential therapeutic targeting.

Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy

“…Another p53-associated DUB, otubain 1 (OTUB1), is expressed in high-grade tumor types, such as lung, breast, and ovarian tumors. OTUB1 regulates p53 to promote tumor cell survival and proliferation [37]. USP42 controls the level of p53 ubiquitination during the early phase of the DDR to promote DNA repair, resulting in the activation of p53-dependent transcription and cell-cycle arrest in response to stress [45].…”

OTUB1 Promotes Progression and Proliferation of Prostate Cancer via Deubiquitinating and Stabling Cyclin E1

“…Furthermore, the status of OTUB1 in the domain of cancer is becoming more and more important and irreplaceable, for example, OTUB1 was found to up-regulated in colorectal cancer (16), gastric adenocarcinoma (17), esophageal cancer (18), ovarian cancer (19), human glioma (20) and hepatocellular carcinoma (21), and promoted tumor invasion and predicted a poor prognosis. OTUB1 promoted tumor progression mainly via two patterns, the one was to stable the expression of tumorigenesis genes by inhibiting ubiquitination of target protein depending on its deubiquitination function, and another mode didn't depend on its deubiquitination manner (22), by direct interacting with E2 ubiquitin ligase. These results implied us that OTUB1 might serve a tumor associated diagnosis biomarker and candidate target for cancer treatment.…”

MicroRNA-103a curtails the stemness of non-small cell lung cancer cells by binding to OTUB1 through the Hippo signaling pathway

“…As a consequence, we postulated that miR-103a exerts regulatory functions over CSCs in NSCLC. Located within locus 11q13.1, ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) is expressed in a great range of human tissues, and OTUB1 knockdown in the A549 cells suppressed soft agar colony formation and xenograft tumor growth [11]. Besides, OTUB1 was revealed as a biomarker in the pathogenesis of gliomas and has the potency to be applied as a clinical biomarker for glioma in the future [12].…”