Redox regulation of DUBs and its therapeutic implications in cancer

Tyagi, Apoorvi; Haq, Saba; Ramakrishna, Suresh

doi:10.1016/j.redox.2021.102194

Cited by 16 publications

(8 citation statements)

References 328 publications

(341 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gene Ontology (GO) analysis of indicated that multiply oxidation-reduction activities and superoxide metabolic process were involved in Kras mutation ( Figure S4 A-B ). Due to homeostasis of redox relies on balance between antioxidant proteins and reactive oxygen species (ROS) 35 , disruption of redox suggests the unbalance of antioxidant and ROS after Kras mutation. Consistently, Wikipathways enrichment analysis furtherly demonstrated that oxidative stress and redox pathway were activated after Kras mutation ( Figure S4 C ).…”

Section: Resultsmentioning

confidence: 99%

Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling

Luo¹,

Liu²,

Fang³

et al. 2022

Theranostics

View full text Add to dashboard Cite

Background & Aims: Abnormal activation of mTOR through loss of tuberous sclerosis complex (Tsc) frequently occurs in hepatocellular carcinoma (HCC). Mutant Kras could induce aggressive HCCs. Here, we aim to identify the predictive or prognostic biomarkers for HCC patients with Kras mutant and mTOR hyperactivation, and to provide potential therapeutic approaches for this subtype of HCCs. Methods: We generated transgenic mice in which hepatocytic mTOR was hyperactivated through Tsc1 insufficiency with or without oncogenic Kras G12D . Bioinformatics and gain- or loss-of-function studies were used to illustrate the mechanisms underlying oncogenic pathway alterations. Transcriptional profiling was used to identify biomarker for the subtype of HCC. The therapeutic efficacy of targeting mTOR was tested in a liver orthotropic homogeneous murine model. Results: Oncogenic Kras G12D facilitated mTOR activation via the Mek/Erk/ROS axis, leading to HCC tumorigenesis and metastasis. Inhibition of Mek/Erk enhanced the anticancer effect of mTOR inhibitor via reduction of mTOR activity. Paternally expressed 3 (PEG3) was responsible for Kras/Erk- and mTOR-driven HCC. Elevated PEG3 protein interacted with STAT3 and promoted its transcriptional activity, resulting in the upregulation of proliferation- and metastasis-related proteins. Targeting mTOR significantly inhibited these actions in vitro and in vivo . Moreover, in clinical samples, PEG3 was identified as a new poor prognostic marker for HCC patients with Kras/Erk and mTOR hyperactivation. Conclusion: These findings reveal the underlying mechanism of hepatocytic Kras/Erk-driven mTOR activation and its downstream targets (PEG3 and STAT3) in HCC, identify PEG3 as a new prognostic biomarker for HCC with Kras/Erk and mTOR hyperactivation, and provide a potential therapeutic strategy for this subset of HCC patients.

show abstract

Section: Resultsmentioning

confidence: 99%

Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling

Luo¹,

Liu²,

Fang³

et al. 2022

Theranostics

View full text Add to dashboard Cite

show abstract

“…Ubiquitination is an important post-translational modification of proteins and participates in a broad range of biological processes through promoting protein degradation. Protein ubiquitination mainly involves an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme and a substrate-specific E3 ubiquitin ligase [ [65] , [66] , [67] ]. TRIMs are a family of E3 ubiquitin ligases and stimulate protein degradation through ubiquitin-proteasome system [ 68 , 69 ].…”

Section: Discussionmentioning

confidence: 99%

TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells

Chen

et al. 2022

Redox Biology

View full text Add to dashboard Cite

“…There are 16 species of cysteine protease OTU family members, which can be divided into four different subfamilies: OTUB subfamilies (OTUB1 and OTUB2), OTUD subfamilies (OTUD1, OTUD2/YOD1, OTUD3, OTUD4, OTUD5/DUBA, OTUD6A, OTUD6B, and ALG13), A20-like subfamilies (A20, Cezanne, Cezanne2, TRABID, and VCPIP), and OTULIN subfamily (OTULIN) ( 31 ). Studies have shown that the Cys catalytic residues present in the OTU subfamily protease active site make it susceptible to reverse oxidation ( 32 ). Here, we introduce the structure and function of “OTUB1 OTUD3 OTUD6B ZRANB1” in the OTU family and the research progress in HCC.…”

Section: Ovarian Tumor Protease Otumentioning

confidence: 99%

Research Progress of DUB Enzyme in Hepatocellular Carcinoma

et al. 2022

View full text Add to dashboard Cite

According to GLOBOCAN 2021 cancer incidence and mortality statistics compiled by the International Agency for Research on Cancer, hepatocellular carcinoma (HCC) is the most common malignancy in the human liver and one of the leading causes of cancer death worldwide. Although there have been great advances in the treatment of HCC, such as regofenib, sorafenib, and lomvatinib, which have been developed and approved for the clinical treatment of advanced or metastatic HCC. However, they only prolong survival by a few months, and patients with advanced liver cancer are susceptible to tumor invasion metastasis and drug resistance. Ubiquitination modification is a type of post-translational modification of proteins. It can affect the physiological activity of cells by regulating the localization, stability and activity of proteins, such as: gene transcription, DNA damage signaling and other pathways. The reversible process of ubiquitination is called de-ubiquitination: it is the process of re-releasing ubiquitinated substrates with the participation of de-ubiquitinases (DUBs) and other active substances. There is growing evidence that many dysregulations of DUBs are associated with tumorigenesis. Although dysregulation of deuquitinase function is often found in HCC and other cancers, The mechanisms of action of many DUBs in HCC have not been elucidated. In this review, we focused on several deubiquitinases (DUBs) associated with hepatocellular carcinoma, including their structure, function, and relationship to hepatocellular carcinoma. hepatocellular carcinoma was highlighted, as well as the latest research reports. Among them, we focus on the USP family and OTU family which are more studied in the HCC. In addition, we discussed the prospects and significance of targeting DUBs as a new strategy for the treatment of hepatocellular carcinoma. It also briefly summarizes the research progress of some DUB-related small molecule inhibitors and their clinical application significance as a treatment for HCC in the future.

show abstract

Redox regulation of DUBs and its therapeutic implications in cancer

Cited by 16 publications

References 328 publications

Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling

Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling

TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells

Research Progress of DUB Enzyme in Hepatocellular Carcinoma

Contact Info

Product

Resources

About