Identification of OTUD6B as a new biomarker for prognosis and immunotherapy by pan-cancer analysis

Abstract

BackgroundOvarian-tumor (OTU) domain-containing protein 6B (OTUD6B), one of newly identified OTU deubiquitylating enzyme families, is proved to be associated with tumor progression. However, whether it plays a key role in pan-cancer still remains unknown.MethodsThe profiles of OTUD6B expression in multiple cancers were analyzed using The Cancer Genome Atlas (TCGA) database. Information of protein expression was performed based on the HPA, GeneCards, and String databases. K-M plotter and survival data analysis were used to analyze the prognostic value of OTUD6B expression, including overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). R package “clusterProfiler” was used for enrichment analysis of OTUD6B. Furthermore, we analyzed the correlation between the expression of OTUD6B, immune infiltration, and immune-related genes. Additionally, we preliminarily validated its tumorigenic effect in lung cancer cell lines.FindingsOTUD6B expression was upregulated in most cancers, such as COAD, CHOL, and LUAD, and predicted poor prognosis in most cancers in TCGA. Results showed that OTUD6B expression was positively correlated with memory CD4+ T cells, Th1 CD4+ T cells, and CD8+ T cells. In terms of the immune-related genes, OTUD6B was found to be associated with most types of genes, such as immunostimulatory genes KDR, TGFBR1, and IL-10. Moreover, for most types of tumors, the immune score was found to be negatively correlated with OTUD6B expression. In addition, lung cancer cell lines with OTUD6B knockdown significantly inhibited proliferation and invasion ability of lung cancer cells.ConclusionsThe study indicated that OTUD6B is an oncogene and may serve as a new potential biomarker in various tumors. OTUD6B may play a part in TIME, which could be applied as a new target for cancer therapy.

Biallelic OTUD6B variants associated with a Kabuki syndrome‐like disorder in three siblings: A clinical report and literature review

“…Adding to the uncertainty, both of the two main isoforms (OTUD6B-1 and OTUD6B-2) could be physiologically relevant in vivo, but with DUB activity that stabilize different cellular substrates resulting in opposing downstream effects as suggested by some reports (Sobol et al, 2017;Straniero et al, 2018). A role for OTUD6B in cell proliferation and/or cell cycle progression (Paulmann et al, 2022;Sobol et al, 2017;Zhao et al, 2022) during mammalian embryonic development and the pathogenesis of OTUD6B-related ND, studies have suggested that it may be involved in global protein synthesis (Sobol et al, 2017), proteasome assembly and function (Santiago-Sim et al, 2017), G1/S cell cycle transition via an OTUD6B-LIN28B-MYC axis as an oncogene (Paulmann et al, 2022), and otud6b appears to negatively regulate antiviral response to viral infection by suppressing Lys-63 ubiquitylation of interferon 3 and 7 (irf3 and irf7) in otud6b-deficient zebrafish (Zhou et al, 2021). Diverse target protein substrates have been proposed.…”

“…Adding to the uncertainty, both of the two main isoforms (OTUD6B‐1 and OTUD6B‐2) could be physiologically relevant in vivo, but with DUB activity that stabilize different cellular substrates resulting in opposing downstream effects as suggested by some reports (Sobol et al, 2017; Straniero et al, 2018). A role for OTUD6B in cell proliferation and/or cell cycle progression (Paulmann et al, 2022; Sobol et al, 2017; Zhao et al, 2022) could potentially explain some of the observed phenotypic effects such as growth deficiency and microcephaly by loss of function disease‐causing variants, though the specific target(s) remain elusive or need confirmation by future studies. By opposing the action of Ub‐ligases, DUBs such as OTUD6B can regulate cellular processes by fine‐tuning the cellular levels of developmental gene products via the UPS.…”

The deubiquitinating protein OTUD6B promotes lung adenocarcinoma progression by stabilizing RIPK1

“…In addition, recent studies have shown that OTUD6B is not only highly expressed in various cancers but also identified and verified that it can be used as a potential predictive biomarker for breast cancer through bioinformatics methods [ 20 ]. At the same time, there are also studies through pancancer analysis that identify OTUD6B as a novel prognostic and immunotherapy biomarker [ 21 ]. Finally, OTUD6B also plays an important role in several diseases other than tumors; for example, biallelic variants in OTUD6B lead to mental retardation syndromes associated with seizures and dysmorphic features [ 22 ]; OTUD6B-AS1 is also a key regulator of apoptosis in systemic sclerosis [ 23 ].…”

Heterogeneity of tumor immune microenvironment in malignant and metastatic change in LUAD is revealed by single-cell RNA sequencing

“…Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer and has the highest cancer mortality rate worldwide [ 1 ]. Immunotherapies had presented sustained clinical significance in LUAD [ 2 ]. However, due to intrinsic genomic and immunogenic heterogeneity, immunotherapy had limited efficacy and the effect for different patients may be inconsistent [ 3 ].…”