USP20 regulates the stability of EMT transcription factor SOX4 and influences colorectal cancer metastasis

Guan, Yu; Jiang, Shi-Ru; Liu, Jun-Guang; Shi, Jirong; Liu, Zhanbing

doi:10.1016/j.prp.2022.153879

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…These results indicated that USP20 is an important regulator of OXA resistance and ferroptosis. We also observed that knockdown or pharmacologically inhibition of USP20 could significantly reduce the proliferation and viability of HCC cells, which was consistent with previous studies 43,64,69–71 . SLC7A11 mediates the cystine/glutamate antiporter activity in the system Xc−, which plays a crucial role in ferroptosis.…”

Section: Discussionsupporting

confidence: 92%

“…We also observed that knockdown or pharmacologically inhibition of USP20 could significantly reduce the proliferation and viability of HCC cells, which was consistent with previous studies. 43 , 64 , 69 , 70 , 71 SLC7A11 mediates the cystine/glutamate antiporter activity in the system Xc−, which plays a crucial role in ferroptosis. The protein stability and turnover of SLC7A11 could be controlled by several ubiquitination manners.…”

Section: Discussionmentioning

confidence: 99%

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ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance

Tang,

Long,

Xiao

et al. 2023

MedComm

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Oxaliplatin (OXA) resistance is a major clinic challenge in hepatocellular carcinoma (HCC). Ferroptosis is a kind of iron‐dependent cell death. Triggering ferroptosis is considered to restore sensitivity to chemotherapy. In the present study, we found that USP20 was overexpressed in OXA‐resistant HCC cells. High expression of USP20 in HCC was associated with poor prognosis. USP20 contributes OXA resistance and suppress ferroptosis in HCC. Pharmacological inhibition or knockdown of USP20 triggered ferroptosis and increased the sensitivity of HCC cells to OXA both in vitro and in vivo. Coimmunoprecipitation results revealed that the UCH domain of USP20 interacted with the N terminal of SLC7A11. USP20 stabilized SLC7A11 via removing K48‐linked polyubiquitination of SLC7A11 protein at K30 and K37. Most importantly, DNA damage‐induced ATR activation was required for Ser132 and Ser368 phosphorylation of USP20. USP20 phosphorylation at Ser132 and Ser368 enhanced its stability and thus conferred OXA and ferroptosis resistance of HCC cells. Our study reveals a previously undiscovered association between OXA and ferroptosis and provides new insight into mechanisms regarding how DNA damage therapies always lead to therapeutic resistance. Therefore, targeting USP20 may mitigate the development of drug resistance and promote ferroptosis of HCC in patients receiving chemotherapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance

Tang,

Long,

Xiao

et al. 2023

MedComm

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“…USP20 has been shown to regulate the stability of SOX4, which is considered an EMT transcription factor. Knockdown of USP20 suppressed cell proliferation, migration, and invasion and decreased the levels of SOX4, N-cadherin, Snail, and Slug but increased the E-cadherin level[ 53 ]. USP22 overexpression enhances colon cancer migration and invasiveness by inducing EMT via activating AP4 (activating enhancer binding protein-4) transcription by binding to its promoter[ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

Al-Balushi,

Al Marzouqi,

Tavoosi

et al. 2024

World J Gastrointest Oncol

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BACKGROUND Colorectal cancer (CRC) is the third most frequent and the second most fatal cancer. The search for more effective drugs to treat this disease is ongoing. A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies. Ubiquitin-specific peptidases (USPs), the largest group of the deubiquitinase protein family, have long been implicated in various cancers. There have been numerous studies on the role of USPs in CRC; however, a comprehensive view of this role is lacking. AIM To provide a systematic review of the studies investigating the roles and functions of USPs in CRC. METHODS We systematically queried the MEDLINE (via PubMed), Scopus, and Web of Science databases. RESULTS Our study highlights the pivotal role of various USPs in several processes implicated in CRC: Regulation of the cell cycle, apoptosis, cancer stemness, epithelial–mesenchymal transition, metastasis, DNA repair, and drug resistance. The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC. The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms. CONCLUSION Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.

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Section: Discussionmentioning

confidence: 99%

“…As is known to all, SOX4 PTMs such as ubiquitination or acetylation not only can impact target gene transcription and expression, but also modulate its function 54,55 . For example, SOX4 deubiquitination regulated by USP20 can control its stability, thereby affecting EMT in colorectal cancer cells, 54 and SOX4‐K95 acetylation can enhance the capacity of SOX4 binding to its target gene 55 . GCN5 is a member of GCN5 related N ‐acetyltransferase family and can acetylate some histone or transcription factors causing transcriptional activity elevation and easily accessing target gene promoters (e.g., GDF15, FGF1, PDGFα, Runx1, and T‐bet) 33,52,53 .…”

Section: Discussionmentioning

confidence: 99%

IL‐17 induces non‐small cell lung cancer metastasis via GCN5‐dependent SOX4 acetylation enhancing MMP9 gene transcription and expression

Wen

Gong

et al. 2023

Molecular Carcinogenesis

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Interleukin‐17 (IL‐17), a potent proinflammatory cytokine, can trigger the metastasis of non‐small cell lung cancer (NSCLC). However, the underlying mechanism involved in IL‐17‐induced NSCLC cell metastasis remains unclear. In this study, we found that not only the expression of IL‐17, IL‐17RA, and/or general control nonrepressed protein 5 (GCN5), SRY‐related HMG‐BOX gene 4 (SOX4), and matrix metalloproteinase 9 (MMP9) was increased in the NSCLC tissues and in the IL‐17‐stimulated NSCLC cells, but also IL‐17 treatment could enhance NSCLC cell migration and invasion. Further mechanism exploration revealed that IL‐17‐upregulated GCN5 and SOX4 could bind to the same region (−915 to −712 nt) of downstream MMP9 gene promoter driving its gene transcription. In the process, GCN5 could mediate SOX4 acetylation at lysine 118 (K118, a newly identified site) boosting MMP9 gene expression as well as cell migration and invasion. Moreover, the SOX4 acetylation or MMP9 induction and metastatic nodule number in the lung tissues of the BALB/c nude mice inoculated with the NSCLC cells stably infected by corresponding LV‐shGCN5 or LV‐shSOX4, LV‐shMMP9 plus IL‐17 incubation were markedly reduced. Overall, our findings implicate that NSCLC metastasis is closely associated with IL‐17‐GCN5‐SOX4‐MMP9 axis.

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USP20 regulates the stability of EMT transcription factor SOX4 and influences colorectal cancer metastasis

Cited by 6 publications

References 29 publications

ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance

ATR‐dependent ubiquitin‐specific protease 20 phosphorylation confers oxaliplatin and ferroptosis resistance

Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

IL‐17 induces non‐small cell lung cancer metastasis via GCN5‐dependent SOX4 acetylation enhancing MMP9 gene transcription and expression

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