USP7 facilitates SMAD3 autoregulation to repress cancer progression in p53-deficient lung cancer

Huang, Yu; Cheng, An Chieh; Tang, Hui Chi; Huang, Guo Cheng; Cai, Ling; Lin, Ta Hsien; Wu, Kou Juey; Tseng, Ping Hui; Wang, Greg G.; Chen, Wei Yi

doi:10.1038/s41419-021-04176-8

Cited by 23 publications

(17 citation statements)

References 54 publications

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“…Based on the Ub chain, Ub modifications could be classified into monoubiquitination (substrate protein tagged with a single Ub molecule) and polyubiquitination (substrate protein tagged with a multiple Ub molecule), and according to the Ub binding sites, ubiquitination are accordingly named K6-, K11-, K27-, K29-, K23-, K48-, and K63linked ubiquitination [36] . Importantly, USP7 can hydrolyze almost all types of Ub through monoubiquitination as well as K48-and K63-linked polyubiquitination [10,37] . Furthermore, USP7 has been shown to markedly reduce the polyubiquitination levels of the substrate proteins, thereby exerting diverse functions [20,38,39] .…”

Section: Usp7 Regulates Diverse Types Of Ubiquitinationmentioning

confidence: 99%

Recent insights into USP7: Construct, pathophysiology, and inhibitors

He¹,

Zhong²,

Wang³

et al. 2022

GPD

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The ubiquitin-proteasome pathway (UPP) is essential for proteostasis and cellular homeostasis. Most of the human proteins are degraded through the UPP in which proteins should be tagged with a specific polyubiquitin chain in a sequential cascade of E1 ubiquitin (Ub)-activating enzymes, namely, E2 Ub-conjugating enzymes and E3 Ub ligases. Meanwhile, the ubiquitination process can be reversed by deubiquitinating enzymes (DUBs), which protect the target proteins from ubiquitination, and so far, around 100 DUBs have been reported to present in human cells. Ubiquitin-specific protease 7 (USP7) is a member of the DUBs family, which has been reported to play crucial role in the development of human tumors and diseases; however, the molecular mechanisms of disease and malignant tumor progression mediated by USP7 has not been fully elucidated. In addition, the therapeutic potential of USP7 in cancer treatment remains to be further explored. Therefore, this review begins with a review of the structure and function of USP7, and then focuses on the development of USP7 inhibitors and their potential applications in various human diseases.

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Section: Usp7 Regulates Diverse Types Of Ubiquitinationmentioning

confidence: 99%

Recent insights into USP7: Construct, pathophysiology, and inhibitors

He¹,

Zhong²,

Wang³

et al. 2022

GPD

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show abstract

“…Also, in LUAD cell lines, inactivation of USP7 induces sensitivity of paclitaxel and docetaxel through degradation of Ki-67 [ 32 ]. However, a recent study reported that inhibition of USP7 reversely induces cell proliferation regulating SMAD3 autoregulation regardless of the p53 axis in p53-deficient lung cancer [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

USP7 regulates the ERK1/2 signaling pathway through deubiquitinating Raf-1 in lung adenocarcinoma

2022

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Ubiquitin-specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUBs) in the ubiquitin-specific protease (USP) family. It is a key regulator of numerous cellular functions including immune response, cell cycle, DNA damage and repair, epigenetics, and several signaling pathways. USP7 acts by removing ubiquitin from the substrate proteins. USP7 also binds to a specific binding motif of substrate proteins having the [P/A/E]-X-X-S or K-X-X-X-K protein sequences. To date, numerous substrate proteins of USP7 have been identified, but no studies have been conducted using the binding motif that USP7 binds. In the current study, we analyzed putative substrate proteins of USP7 through the [P/A/E]-X-X-S and K-X-X-X-K binding motifs using bioinformatics tools, and confirmed that Raf-1 is one of the substrates for USP7. USP7 binds to the Pro-Val-Asp-Ser (PVDS) motif of the conserved region 2 (CR2) which contains phosphorylation sites of Raf-1 and decreased M1-, K6-, K11-, K27-, K33-, and K48-linked polyubiquitination of Raf-1. We further identified that the DUB activity of USP7 decreases the threonine phosphorylation level of Raf-1 and inhibits signaling transduction through Raf activation. This regulatory mechanism inhibits the activation of the ERK1/2 signaling pathway, thereby inhibiting the G2/M transition and the cell proliferation of lung adenocarcinoma cells. In summary, our results indicate that USP7 deubiquitinates Raf-1 and is a new regulator of the ERK1/2 signaling pathway in lung adenocarcinoma.

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“…The role of the canonical transforming growth factor beta (TGF‐β) signaling pathway is well established in multiple physiological and pathological processes, and its constituent members include a ligand (TGF‐β1), two receptors (TGFBR1 and TGFBR2), and three SMADs (SMAD2, SMAD3, and SMAD4), which are involved in transferring extracellular TGF‐β signals to the nucleus, and regulating the expression of target genes (Du et al, 2018). Furthermore, the canonical TGF‐β signaling pathway is controlled by transcriptional regulation (Ammous et al, 2021; Wang et al, 2021), posttranscriptional regulation (Zhang et al, 2021), and PTMs (Huang et al, 2021). Among the important PTMs, ubiquitination and deubiquitination play critical roles in regulation of the TGF‐β signaling pathway in various cell types and tissues (Dupont et al, 2009; Eichhorn et al, 2012; Huang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the canonical TGF‐β signaling pathway is controlled by transcriptional regulation (Ammous et al, 2021; Wang et al, 2021), posttranscriptional regulation (Zhang et al, 2021), and PTMs (Huang et al, 2021). Among the important PTMs, ubiquitination and deubiquitination play critical roles in regulation of the TGF‐β signaling pathway in various cell types and tissues (Dupont et al, 2009; Eichhorn et al, 2012; Huang et al, 2021). The receptors and SMAD members involved in the canonical TGF‐β signaling pathway have been identified as the substrates of different E3 ubiquitin ligases and deubiquitylases (Chen et al, 2020; Li et al, 2019; Shrestha et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the canonical TGF-β signaling pathway is controlled by transcriptional regulation (Ammous et al, 2021;Wang et al, 2021), posttranscriptional regulation (Zhang et al, 2021), and PTMs (Huang et al, 2021). Among the important PTMs, ubiquitination and deubiquitination play critical roles in regulation of the TGF-β signaling pathway in various cell types and tissues (Dupont et al, 2009;Eichhorn et al, 2012;Huang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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TGFBR2 is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells

Yang

Wang

Pan

et al. 2022

Journal Cellular Physiology

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The ubiquitin‐specific peptidase 9 X‐linked (USP9X) is one of the highly conserved members belonging to the ubiquitin‐specific proteases (USPs) family, which has been reported to control substrates‐mediated biological functions through deubiquitinating and stabilizing substrates. Here, we have found that TGFBR2, the type II receptor of the transforming growth factor beta (TGF‐β) signaling pathway, is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells (GCs). Mechanically, USP9X positively influences the expression of TGFBR2 at different levels through two independent ways: (i) directly targets and deubiquitinates TGFBR2, which maintains the protein stability of TGFBR2 through avoiding degradation mediated by ubiquitin‐proteasome system; (ii) indirectly maintains TGFBR2 messenger RNA (mRNA) expression via SMAD4/miR‐143 axis. Specifically, SMAD4, another substrate of USP9X, acts as a transcription factor and suppresses miR‐143 which inhibits the mRNA level of TGFBR2 by directly binding to its 3′‐untranslated region. Functionally, the maintenance of TGFBR2 by USP9X activates the TGF‐β signaling pathway, which further represses GC apoptosis. Our study highlights a functional micro‐regulatory network composed of deubiquitinase (USP9X), small noncoding RNA (miR‐143) and the TGF‐β signaling pathway, which plays a crucial role in the regulation of GC apoptosis and female fertility.

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USP7 facilitates SMAD3 autoregulation to repress cancer progression in p53-deficient lung cancer

Cited by 23 publications

References 54 publications

Recent insights into USP7: Construct, pathophysiology, and inhibitors

Recent insights into USP7: Construct, pathophysiology, and inhibitors

USP7 regulates the ERK1/2 signaling pathway through deubiquitinating Raf-1 in lung adenocarcinoma

TGFBR2 is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells

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