RETRACTED: OTUB2 Facilitates Tumorigenesis of Gastric Cancer Through Promoting KDM1A-Mediated Stem Cell-Like Properties

Abstract

Otubain 2 (OTUB2), a deubiquitinating enzyme, overexpression is considered to predict poor outcome in various cancers. However, the function and potential regulatory mechanisms of OTUB2 in gastric cancer (GC) progression remains unclear. To determine how OTUB2 participate in GC progression, the gain and loss of-function experiments were conducted in vivo and in vitro. We found that OTUB2 was upregulated in GC samples (n=140) and cells. Moreover, the overall, first progression and post progression survival rates of GC patients with high OTUB2 expression showed a poorer prognosis than that in those patients with low OTUB2 expression. Down-regulation of OTUB2 suppressed sphere formation and reduced expression of stem cell markers in GC cells. Furthermore, OTUB2-silenced GC cells also showed a decreased proliferation, invasion, migration, and in vivo tumorigenic ability. However, OTUB2 overexpression showed the opposite effects. Notably, we demonstrated that OTUB2 increased lysine-specific histone demethylase 1A (KDM1A) expression through deubiquitination. KDM1A, a demethylase known to promote demethylation of downstream genes, was identified to promote the maintenance of cancer stem cell characteristics. Moreover, the alterations caused by OTUB2 overexpression were partly inversed by KDM1A knockdown and in turn KDM1A overexpression reversed the changes induced by OTUB2 shRNA. Taken together, we demonstrate that OTUB2 may serve as a vital driver in GC tumorigenesis by enhancing KDM1A-mediated stem cell-like properties.

The Emerging Role of OTUB2 in Diseases: From Cell Signaling Pathway to Physiological Function

“…For example, in gastric cancer cells, OTUB2 can deubiquitinate the lysine specific demethylase 1A (KDM1A, not only can demethylate histones, but also p53, DNA methyltransferase, etc.) to promote gastric cancer cell proliferation, migration, and invasion ( Huang et al, 2007 ; Lan et al, 2008 ; Wang et al, 2009 ; Liu et al, 2021 ). However, due to insufficient research and the molecular mechanism of some diseases has not yet been elucidated, the current understanding of OTUB2 is not comprehensive.…”

“…Although OTUB2 is theoretically overexpressed in diseases such as cancers, its basic expression in normal cells should also be considered. However, the expression of OTUB2 is rather low in normal tissue, and targeted inhibition will not affect cell apoptosis, differentiation at the cellular level ( Liu et al, 2021 ). This may be due to the powerful compensatory supplementation of DUBs in vivo .…”

Research Progress for Targeting Deubiquitinases in Gastric Cancers

“…OTUB1 was found to be active in GC cell invasion and migration [ 89 ], but the underlying mechanism is unknown. Similar to OTUB1, OTUB2 was also found to be overexpressed in GC tissues and cell lines and predicted a poor prognosis [ 90 , 91 ]. Silencing OTUB2 inhibited GC cell growth, metastasis, and sphere formation.…”

“…Silencing OTUB2 inhibited GC cell growth, metastasis, and sphere formation. Mechanistically, OTUB2 acts as a potential driver oncogene in GC by deubiquitinating and stabilizing the demethylase KDM1A, and epithelial keratin KRT80 [ 90 , 91 ]. As previously reported, KDM1A and KRT80 contributed to GC progression by regulating KLF2 expression and the PI3K/Akt pathway, respectively [ 172 , 173 ].…”

The Deubiquitinase USP13 Maintains Cancer Cell Stemness by Promoting FASN Stability in Small Cell Lung Cancer

“…Protein ubiquitination, post-translational modification that regulates all kinds of cellular biological processes, is counteracted upon deubiquitylation by deubiquitinating enzymes (DUBs). DUBs played crucial role in CSC maintenance and differentiation through the regulation of core stem cell transcription factors (SCTFs), such as Oct4, Nanog, and the stem cell surface marker CD133 along with cancer cell sphere formation ability (13)(14)(15)(16). In more than one hundred DUBs, ubiquitin-specific proteases (USPs) subfamily is the largest and the most widely studied member.…”