pVHL-mediated SMAD3 degradation suppresses TGF-β signaling

Zhou, Jun; Dabiri, Yasamin; Gama-Brambila, Rodrigo A.; Ghafoory, Shahrouz; Altinbay, Mukaddes; Mehrabi, Arianeb; Golriz, Mohammad; Blagojevic, Biljana; Reuter, Stefanie; Han, Kang; Seidel, Anna; Đikić, Ivan; Wölfl, Stefan; Cheng, Xinlai

doi:10.1083/jcb.202012097

Cited by 15 publications

(9 citation statements)

References 66 publications

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“… 48 Recent study reported by this team further demonstrated that pVHL (a component of an E3 ubiquitin ligase complex) also contributes for SMAD ubiquitination degradation induced by indirubin treatment. 49 Consistent with that, our study shows that Ub-specific processing proteases pathway (UPP pathway) was notably suppressed after I3MO treatment in a panel of MM cell lines. I3MO treatment significantly suppresses the expressions of USP7, USP11, USP13, USP18, UBB, and UBC etc.…”

Section: Discussionsupporting

confidence: 91%

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

Wei

Liu

et al. 2022

eBioMedicine

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Section: Discussionsupporting

confidence: 91%

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

Wei

Liu

et al. 2022

eBioMedicine

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“…Considering the restricted regulatory effect of limited exogenous DJ-1, we inferred that there may be a positive feedback loop and DJ-1 probably acts as a catalyst. Smad3 has been widely recognized as an important transcription factor, especially transducing signals from TGF-β superfamily ligands, thus entering the nucleus and activating the transcription of a series of oncogenes [22]. In our study, western blot results suggested that with the passage of time (0-240 min), the ratio of p-Smad3/Smad3 gradually stabilized, and the expression of TSP1, TGF-β1, and MMPs gradually increased in K150 cells (Fig.…”

Section: Smad3 Transcribes Thbs1 To Accelerate the Metastasis Of K150...supporting

confidence: 52%

Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop

Sun

Song

et al. 2022

J Exp Clin Cancer Res

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Background Radiation-induced bystander effect (RIBE) can promote tumor metastasis contributing to the failure of radiotherapy for esophageal squamous cell carcinoma (ESCC). Aberrant expression of DJ-1 has been identified in ESCC; however, the relationship between DJ-1 and RIBE in ESCC remains unknown. Methods We detected DJ-1 in the serum and cell supernatants by enzyme-linked immunosorbent assay (ELISA) and evaluated tumor metastasis by phenotypic experiments in vivo and in vitro. RNA-seq, mass spectrometry, western blot (WB), immunoprecipitation (IP), and dual-luciferase reporter assays were performed to explore the underlying mechanisms. Results DJ-1 was highly expressed in the serum of patients with ESCC receiving radiotherapy and was significantly overexpressed in the medium of ESCC cells receiving irradiation. DJ-1 promoted tumor metastasis via the TGF-β1 pathway. Mechanistic studies revealed that DJ-1 bound to HSC70 to promote Smad3 phosphorylation and nuclear aggregation in a protein-interaction manner, which activated the transcription of Thrombospondin-1 (TSP1). Subsequently, the activation of TGF-β1 by TSP1 re-promoted Smad3 phosphorylation and nuclear aggregation, constituting a positive feedback loop to strengthen the metastasis of ESCC cells, which was effectively blocked by LY2109761 and LSKL. Moreover, higher levels of serum DJ-1 in patients with ESCC were related to a poorer prognosis of radiotherapy. Conclusions Irradiation can induce ESCC cells secreting DJ-1. Secreted DJ-1 enters bystander cells to initiate activation of the TGF-β1 pathway via the DJ-1/HSC70/Smad3 signaling axis. The TSP1/TGF-β1/Smad3 positive feedback pathway constitutes the core pathway that promotes ESCC metastasis. DJ-1 is a useful biomarker for predicting the efficacy of radiotherapy and a potential therapeutic target for reversing RIBE in ESCC. Graphical Abstract Schematic diagram showing the underlying mechanism that irradiation-induced secretion of DJ-1 accelerates the metastasis of bystander ESCC cells.

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“…The expression of SETD2 and VHL is positively correlated in patients with renal fibrosis and renal cancer, indicating their clinical significance. Available studies have suggested that VHL protein can also ubiquitinate Smad3 56,57 . In this study, we found that SETD2 and VHL could jointly inhibit TGF‐β/Smad signalling pathway activation.…”

Section: Discussionmentioning

confidence: 51%

SETD2 deficiency promotes renal fibrosis through the TGF‐β/Smad signalling pathway in the absence of VHL

Liu,

Ni,

et al. 2023

Clinical & Translational Med

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BackgroundRenal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. Epigenetic alteration is a significant intrinsic factor contributing to the development of renal fibrosis. SET domain‐containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalysing H3K36 trimethylation. There is evidence that SETD2‐mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis.MethodsKidney tissues from mice as well as HK2 cells were used as research subjects. Clinical databases of patients with renal fibrosis were analysed to investigate whether SETD2 expression is reduced in the occurrence of renal fibrosis. SETD2 and Von Hippel–Lindau (VHL) double‐knockout mice were used to further investigate the role of SETD2 in renal fibrosis. Renal tubular epithelial cells isolated from mice were used for RNA sequencing and chromatin immunoprecipitation sequencing to search for molecular signalling pathways and key molecules leading to renal fibrosis in mice. Molecular and cell biology experiments were conducted to analyse and validate the role of SETD2 in the development of renal fibrosis. Finally, rescue experiments were performed to determine the molecular mechanism of SETD2 deficiency in the development of renal fibrosis.ResultsSETD2 deficiency leads to severe renal fibrosis in VHL‐deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the transforming growth factor‐β (TGF‐β)/Smad signalling pathway, thereby preventing the activation of the TGF‐β/Smad signalling pathway. Deletion of SETD2 leads to reduced Smad7 expression, which results in activation of the TGF‐β/Smad signalling pathway and ultimately renal fibrosis in the absence of VHL.ConclusionsOur findings reveal the role of SETD2‐mediated H3K36me3 of Smad7 in regulating the TGF‐β/Smad signalling pathway in renal fibrogenesis and provide an innovative insight into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.

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pVHL-mediated SMAD3 degradation suppresses TGF-β signaling

Cited by 15 publications

References 66 publications

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

Indirubin-3’-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma

Irradiation induces DJ-1 secretion from esophageal squamous cell carcinoma cells to accelerate metastasis of bystander cells via a TGF-β1 positive feedback loop

SETD2 deficiency promotes renal fibrosis through the TGF‐β/Smad signalling pathway in the absence of VHL

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