RHBDL2 promotes the proliferation, migration, and invasion of pancreatic cancer by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway

Chen, Shiyu; Cai, Kun; Zheng, Dijie; Liu, Yanqing; Li, Lin; He, Zhiwei; Sun, Cheng-Yi; Yu, Chao

doi:10.1038/s41419-022-05379-3

Cited by 12 publications

(9 citation statements)

References 40 publications

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“…However, these genes have also been reported to be associated with the occurrence and development of other types of tumors. For example, OTUD7B has been reported to play a critical role in activating mTORC2/AKT signaling and promoting lung cancer, [ 27 ] and its abnormal expression is also associated with the progression of breast cancer, [ 28 ] pancreatic cancer, [ 29 ] and liver cancer. [ 30 ] High expression of AP1S3 is closely related to the proliferation, invasion, and migration of glioma cells.…”

Section: Discussionmentioning

confidence: 99%

Development and evaluation of an adenosine-to-inosine RNA editing-based prognostic model for survival prediction of bladder cancer patients

et al. 2023

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Adenosine-to-inosine RNA editing (ATIRE) is a common form of ribonucleic acid (RNA) editing, which has highlighted the importance of ATIRE in tumors. However, its role in bladder cancer (BLCA) remains poorly understood. To study ATIRE impact on BLCA patient prognosis, we obtained ATIRE, gene expression, and clinical data from the Cancer Genome Atlas (TCGA) database for 251 patients, randomly dividing them into training and testing groups. Univariate proportional hazards model (COX) regression identified prognosis-associated ATIRE loci, while the least absolute shrinkage and selection operator (LASSO) selected final loci to construct prognostic models and generate ATIRE scores. We developed a nomogram to predict BLCA patients’ overall survival (OS) and analyzed the effect of ATIRE editing levels on host gene expression. We also compared immune cell infiltration and drug treatment between patients with high and low ATIRE scores. The ATIRE prognostic prediction model was constructed using ten ATIRE loci that are closely associated with BLCA survival. Patients with high ATIRE scores showed significantly worse OS than those with low ATIRE scores. Furthermore, the nomogram, which incorporates the ATIRE score, can better predict the prognosis of patients. Multiple functional and pathway changes associated with immune responses, as well as significant differences in immune cell infiltration levels and response to drug therapy were observed between patients with high and low ATIRE scores. This study represented the first comprehensive analysis of the role of ATIRE events in BLCA patient prognosis and provided new insights into potential prognostic markers for BLCA research.

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Section: Discussionmentioning

confidence: 99%

Development and evaluation of an adenosine-to-inosine RNA editing-based prognostic model for survival prediction of bladder cancer patients

et al. 2023

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“…Dysregulation of OTUD7B has been observed in several types of cancer, such as lung, breast, liver, and pancreatic cancers. In these cancers, the upregulation of OTUD7B promotes the stabilization and activation of TRAF3, estrogen receptor α, and N1ICD, leading to uncontrolled cell growth and tumor formation [ 31 , 32 , 33 , 34 , 35 , 36 ]. Conversely, downregulation of OTUD7B has been associated with impaired DNA damage response and increased genomic instability [ 29 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

OTUD7B Activates Wnt Signaling Pathway through the Interaction with LEF1

2023

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The Wnt signaling pathway plays a critical role in regulating normal cellular processes, including proliferation, differentiation, and apoptosis. Dysregulation of Wnt signaling has been implicated in various human diseases, including cancer. β-catenin and LEF1 are key mediators of Wnt signaling, and their dysregulation is a hallmark of many cancer types. In this study, we aimed to identify the deubiquitinases (DUBs) that regulate the Wnt signaling pathway through the essential component LEF1. Screening candidate DUBs from the human DUB library, we discovered that OTUD7B interacts with LEF1 and activates Wnt signaling. OTUD7B and LEF1 interact with each other through the UBA and HMG domains, respectively. Furthermore, OTUD7B promotes the nuclear localization of LEF1, leading to an increased interaction with β-catenin in the nucleus while not noticeably affecting ubiquitination on LEF1. Using qPCR array analysis, we found that OTUD7B overexpression leads to an upregulation of 75% of the tested Wnt target genes compared to the control. These findings suggest that OTUD7B may serve as a potential therapeutic target in human diseases, including cancers where Wnt signaling is frequently dysregulated.

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“…As a deubiquitinating enzyme (DUB), it regulates many important cellular signaling pathways, such as those related to inflammation, scar formation, and T cell activation 16,17 . Accumulating data suggested that OTUD7B expression directly affected the survival rate of various solid tumors, such as lung cancer, liver cancer, breast cancer, or pancreatic cancer, and played a potential role in cancer cell proliferation 18–21 . It has recently been shown that OTUD7B attenuates the ubiquitination level of N1ICD (Notch1 intracellular domain) by binding to RHBDL2 (rhomboid‐like 2 protein), thereby activating Notch signaling 18 …”

Section: Introductionmentioning

confidence: 99%

“…16,17 Accumulating data suggested that OTUD7B expression directly affected the survival rate of various solid tumors, such as lung cancer, liver cancer, breast cancer, or pancreatic cancer, and played a potential role in cancer cell proliferation. [18][19][20][21] It has recently been shown that OTUD7B attenuates the ubiquitination level of N1ICD (Notch1 intracellular domain) by binding to RHBDL2 (rhomboid-like 2 protein), thereby activating Notch signaling. 18 Based on the above findings, we sought to elucidate a novel mechanism by which OTUD7B inhibits lung cancer fine progression under hyperthermia conditions, and provide new insights into the occurrence and development of lung cancer and anti-tumor therapy.…”

mentioning

confidence: 99%

“…[18][19][20][21] It has recently been shown that OTUD7B attenuates the ubiquitination level of N1ICD (Notch1 intracellular domain) by binding to RHBDL2 (rhomboid-like 2 protein), thereby activating Notch signaling. 18 Based on the above findings, we sought to elucidate a novel mechanism by which OTUD7B inhibits lung cancer fine progression under hyperthermia conditions, and provide new insights into the occurrence and development of lung cancer and anti-tumor therapy.…”

mentioning

confidence: 99%

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OTU deubiquitinase 7B facilitates the hyperthermia‐induced inhibition of lung cancer progression through enhancing Smac‐mediated mitochondrial dysfunction

Sun,

Bai,

Sun

et al. 2023

Environmental Toxicology

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Hyperthermia, as an adjuvant therapy, has shown promising anti‐tumor effects. Ovarian tumor domain‐containing 7B (OTUD7B) is a deubiquitinating enzyme that is frequently found in a variety of cancers. The aim of this study is to investigate the role of OTUD7B in lung cancer hyperthermia and the underlying mechanism. A549 and CALU‐3 cells were respectively exposed to 42 or 44°C for the indicated times (0, 1, 3, or 6 h) followed by incubation at 37°C for 24 h. We found a temperature‐ and time‐dependent decrease in cell viability and an increase in apoptosis levels. Compared with 0 h, heat treatment for 3 h inhibited the proliferation and invasion of A549 cells, reduced the expression levels of mitochondrial membrane potential, IAP family members (cIAP‐1 and XIAP) proteins and ubiquitination of Smac, and increased Smac protein expression. Treatment with 10 μM Smac mimic BV6 further enhanced the anti‐tumor effect of hyperthermia. Next, co‐IP validation showed that OTUD7B interacted with Smac and stabilized Smac through deubiquitination. OTUD7B overexpression induced damage in A549 and CALU‐3 cells, while silencing OTUD7B caused opposite effects. Overexpressing OTUD7B enhanced the anti‐cancer effect of hyperthermia, while si‐OTUD7B reversed the anti‐cancer effect of hyperthermia, which was verified in the xenograft tumor model in nude mice. Taken together, OTUD7B may serve as a potential anticancer factor with potential clinical efficacy in the thermotherapeutic treatment of lung cancer.

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RHBDL2 promotes the proliferation, migration, and invasion of pancreatic cancer by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway

Cited by 12 publications

References 40 publications

Development and evaluation of an adenosine-to-inosine RNA editing-based prognostic model for survival prediction of bladder cancer patients

Development and evaluation of an adenosine-to-inosine RNA editing-based prognostic model for survival prediction of bladder cancer patients

OTUD7B Activates Wnt Signaling Pathway through the Interaction with LEF1

OTU deubiquitinase 7B facilitates the hyperthermia‐induced inhibition of lung cancer progression through enhancing Smac‐mediated mitochondrial dysfunction

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