USP5 facilitates non-small cell lung cancer progression through stabilization of PD-L1

Pan, Jinghua; Qiao, Yiting; Chen, Congcong; Zang, Hongjing; Zhang, Xiaojing; Qi, Feng; Chang, Cunjie; Yang, Fan; Sun, Mengqing; Lin, Shengbin; Tang, Quandong; Li, Lina; Wang, Menglan; Wu, Minjie; Liu, Yongzhu; Lai, Caiyong; Chen, Jianxiang; Guo, Cheng

doi:10.1038/s41419-021-04356-6

Cited by 38 publications

(21 citation statements)

References 32 publications

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“…Abundant evidence indicates that USP5 expression is elevated in NSCLC cancers 13 , 17 – 19 , while the correlation of Beclin 1 protein expression with NSCLC remains debatable 37 . We thus examined the expression of USP5 and Beclin 1 in human lung adenocarcinoma biopsy samples and paired adjacent tissue via IHC, followed by analyses of Average Optical Density (AOD) 38 .…”

Section: Resultsmentioning

confidence: 99%

USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity

Wang

Luo

et al. 2022

Nat Commun

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Non-small cell lung cancers (NSCLC) frequently contain KRAS mutation but retain wild-type TP53. Abundant senescent cells are observed in premalignant but not in malignant tumors derived from the Kras-driven mouse model, suggesting that KRAS oncogenic signaling would have to overcome the intrinsic senescence burden for cancer progression. Here, we show that the nuclear Beclin 1-mediated inhibition of p53-dependent senescence drives Kras-mediated tumorigenesis. KRAS activates USP5 to stabilize nuclear Beclin 1, leading to MDM2-mediated p53 protein instability. KrasG12D mice lacking Beclin 1 display retarded lung tumor growth. Knockdown of USP5 or knockout of Becn1 leads to increased senescence and reduced autophagy. Mechanistically, KRAS elevates ROS to induce USP5 homodimer formation by forming the C195 disulfide bond, resulting in stabilization and activation of USP5. Together, these results demonstrate that activation of the USP5-Beclin 1 axis is pivotal in overriding intrinsic p53-dependent senescence in Kras-driven lung cancer development.

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Section: Resultsmentioning

confidence: 99%

USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity

Wang

Luo

et al. 2022

Nat Commun

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“…Ubiquitination assay was carried out following a previously published method [ 28 ]. Briefly, the cells were resuspended in the lysis buffer containing protease inhibitor and subjected to ultrasonic lysing.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of OTUD5 in non‐small cell lung cancer cell proliferation, invasion, and migration

Zhang

et al. 2022

Bosn J of Basic Med Sci

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Ovarian tumor protease deubiquitinase 5 (OTUD5) has been discussed as a regulator of cancer development. Herein, the current study set out to explore the molecular mechanism of OTUD5 in non‐small cell lung cancer (NSCLC) cell proliferation, invasion, and migration. Firstly, the expression patterns of OTUD5, phosphatase and tensin homolog (PTEN), as well as microRNA (miR)-652-3p in cells were detected by qRT-PCR and Western blot. Cell viability, migration, and invasion were assessed with the help of cell-counting kit-8 and Transwell assays, in addition to the measurement of the ubiquitination and protein levels of PTEN. The binding relations between OTUD5 and PTEN, and miR-652-3p and OTUD5 were testified by co-immunoprecipitation or dual-luciferase assays. Cells were further treated with GSK2643943A (inhibitor of deubiquitinase) or miR-652-3p-inhibitor to explore the role of PTEN ubiquitination and miR-652-3p in NSCLC cells. OTUD5 and PTEN were both poorly-expressed, and miR-652-3p was highly-expressed in NSCLC cells. On the other hand, over-expression of OTUD5 suppressed NSCLC cell proliferation, invasion, and migration. OTUD5 deubiquitinated and stabilized PTEN, and miR-652-3p targeted and inhibited OTUD5 expression. Augmenting the ubiquitination levels of PTEN promoted NSCLC cell growth, whereas miR-652-3p inhibition promoted the tumor-suppressing effects of the OTUD5/ PTEN axis in NSCLC. Altogether, our findings highlighted that miR-652-3p restrained the role of OTUD5 in deubiquitinating PTEN to improve PTEN protein level, thereby promoting NSCLC cell proliferation, invasion, and migration.

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“…Programmed death ligand-1 (PD-L1) is a crucial immune checkpoint molecule and downregulates T-cell immune responses by binding to programmed death protein-1 (PD-1). Emerging evidence indicates that the protein stabilization of PD-L1 is regulated by several DUBs, such as USP5, USP22, and USP9X ( Hu et al, 2021 ; Pan et al, 2021 ). Notably, a recent study found that USP21 could also deubiquitylate and stabilize PD-L1, suggesting a potential role of USP21 in immunosuppression ( Yang et al, 2021 ).…”

Section: Role Of Usp21 In Diverse Biological Processesmentioning

confidence: 99%

Insights Into the Properties, Biological Functions, and Regulation of USP21

et al. 2022

Front. Pharmacol.

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Deubiquitylating enzymes (DUBs) antagonize ubiquitination by removing ubiquitin from their substrates. The role of DUBs in controlling various physiological and pathological processes has been extensively studied, and some members of DUBs have been identified as potential therapeutic targets in diseases ranging from tumors to neurodegeneration. Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease family, the largest subfamily of DUBs. Although USP21 was discovered late and early research progress was slow, numerous studies in the last decade have gradually revealed the importance of USP21 in a wide variety of biological processes. In particular, the pro-carcinogenic effect of USP21 has been well elucidated in the last 2 years. In the present review, we provide a comprehensive overview of the current knowledge on USP21, including its properties, biological functions, pathophysiological roles, and cellular regulation. Limited pharmacological interventions for USP21 have also been introduced, highlighting the importance of developing novel and specific inhibitors targeting USP21.

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USP5 facilitates non-small cell lung cancer progression through stabilization of PD-L1

Cited by 38 publications

References 32 publications

USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity

USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity

Mechanism of OTUD5 in non‐small cell lung cancer cell proliferation, invasion, and migration

Insights Into the Properties, Biological Functions, and Regulation of USP21

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