Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7

Zhang, Zhengkui; Yao, Fan; Xie, Feng; Zhou, Hang; Jin, Ke; Shao, Li; Shi, Wenhao; Fang, Pengfei; Yang, Bing; Dam, Hans van; Dijke, Peter ten; Zheng, Xiaofeng; Yan, Xiaohua; Jia, Junling; Zheng, Min; Jin, Jin; Ding, Chen; Ye, Sheng; Zhou, Fangfang; Zhang, Long

doi:10.1038/s41467-017-02029-7

Cited by 94 publications

(81 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After the indicated days/weeks, all mice were killed and lung metastases were analyzed. Mouse nipple implantation was based on a previously published method (Zhang et al, 2017b). Female BALB/c mice were anesthetized and used for this assay.…”

Section: Mice Metastasis Modelsmentioning

confidence: 99%

OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ

et al. 2019

Self Cite

View full text Add to dashboard Cite

Graphical Abstract Highlights d OTUB2 enhances metastasis through Hippo-independent activation of YAP/TAZ signaling d Poly-SUMOylation is required for OTUB2 to interact with and deubiquitinate YAP/TAZ d YAP/TAZ contain a SUMO-interacting motif (SIM) required for binding SUMOylated OTUB2 d EGF treatment or KRAS mutation stabilizes YAP/TAZ by stimulating OTUB2 SUMOylation In Brief Zhang et al. identified OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ independent of the Hippo signaling. OTUB2 was induced by EGF/KRAS to be poly-SUMOylated on lysine 233, and this SUMOylation enables it to bind YAP/TAZ through a yetunknown SUMO-interacting motif (SIM). SUMMARY The transcriptional regulators YAP and TAZ play important roles in development, physiology, and tumorigenesis and are negatively controlled by the Hippo pathway. It is yet unknown why the YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active.Here, by a gain-of-function cancer metastasis screen, we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on lysine 233, and this SUMOylation enables it to bind YAP/TAZ. We also identified a yetunknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activate YAP/TAZ. Our results establish OTUB2 as an essential modulator of YAP/TAZ and also reveal a novel mechanism via which YAP/TAZ activity is induced by oncogenic KRAS.

show abstract

Section: Mice Metastasis Modelsmentioning

confidence: 99%

OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tumor metastasis is usually associated with abnormal expression of cytokines, especially CXCL12 [42][43][44][45][46], VEGF [47,48], IL1β [49,50], and IL6 [51,52], while CAFs can promote tumor growth and invasion via a plethora of active factors [53]. We therefore checked these specific cytokines in different cancer cells with the presence or absence of different NF-CMs.…”

Section: Discussionmentioning

confidence: 99%

GATA3 suppresses human fibroblasts-induced metastasis of clear cell renal cell carcinoma via an anti-IL6/STAT3 mechanism

Shi

Song

et al. 2019

Cancer Gene Ther

View full text Add to dashboard Cite

Tumorigenesis and metastasis depend on intricate interactions between genetically altered tumor cells and their surrounding microenvironment. It is, however, unclear regarding the molecular mechanisms underlying the progress and metastasis of human clear-cell renal cell carcinoma in the microenvironment with fibroblasts. In this work, we investigated the effect of normal fibroblasts on the metastasis of renal cancer and the relevant signaling pathways. We isolated normal fibroblasts from normal renal tissues and used normal fibroblast-conditioned medium culture renal cancer cells. The CCK-8 and transwell assays showed that normal fibroblasts conditioned medium significantly enhanced ccRCC cell migration. IL6 mediated the cross talk between normal fibroblasts and the cancer cells, and promoted tumor cell migration through the STAT3 pathway. In contrast, GATA3 was downregulated at both mRNA and protein levels in the normal fibroblast-conditioned medium treated with renal cancer cells, but upregulated in adjacent normal tissues. GATA3 overexpression significantly reduced STAT3 phosphorylation and attenuated the migration in both renal cancer cell and IL6-stimulated renal cancer cell. Taken together, our findings suggest that the IL6/STAT3 pathway plays a crucial role in the normal fibroblast-enhanced clear-cell renal cell carcinoma metastasis, while GATA3 may mitigate this effect by inhibiting IL6/STAT3 signaling.

show abstract

“…32 the two inhibitory Smads have been shown critical in controlling TGF-β/BMP signaling through negative feedback mechanisms. 36,[45][46][47][48] We found that overexpression of the CXXC5 protein in both HCC cells and normal hepatocyte cell lines promotes TGF-β-induced luciferase reporter expression, while knockdown of CXXC5 gene ameliorates it. Moreover, transcriptional profiling indicates that depletion of CXXC5 in Hep3B HCC cells is able to attenuate the expression of a significant portion of TGF-β target genes, suggesting that CXXC5 is a novel positive feedback regulator of TGF-β signaling.…”

Section: Cxxc5 In Tgf-β/bmp Signalingmentioning

confidence: 82%

“…Feedback regulation plays a pivotal role, fine‐tuning signaling robustness and duration . With respect to it, the two inhibitory Smads have been shown critical in controlling TGF‐β/BMP signaling through negative feedback mechanisms . We found that overexpression of the CXXC5 protein in both HCC cells and normal hepatocyte cell lines promotes TGF‐β‐induced luciferase reporter expression, while knockdown of CXXC5 gene ameliorates it.…”

Section: Cxxc5 Functions As a Signaling Regulator And Mediatormentioning

confidence: 83%

CXXC5: A novel regulator and coordinator of TGF‐β, BMP and Wnt signaling

Xiong

Wang

et al. 2018

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

CXXC5 is a member of the CXXC‐type zinc‐finger protein family. Proteins in this family play a pivotal role in epigenetic regulation by binding to unmethylated CpG islands in gene promoters through their characteristic CXXC domain. CXXC5 is a short protein (322 amino acids in length) that does not have any catalytic domain, but is able to bind to DNA and act as a transcription factor and epigenetic factor through protein‐protein interactions. Intriguingly, increasing evidence indicates that expression of the CXXC5 gene is controlled by multiple signaling pathways and a variety of transcription factors, positioning CXXC5 as an important signal integrator. In addition, CXXC5 is capable of regulating various signal transduction processes, including the TGF‐β, Wnt and ATM‐p53 pathways, thereby acting as a novel and crucial signaling coordinator. CXXC5 plays an important role in embryonic development and adult tissue homeostasis by regulating cell proliferation, differentiation and apoptosis. In keeping with these functions, aberrant expression or altered activity of CXXC5 has been shown to be involved in several human diseases including tumourigenesis. This review summarizes the current understanding of CXXC5 as a transcription factor and signaling regulator and coordinator.

show abstract

Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7

Cited by 94 publications

References 63 publications

OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ

OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ

GATA3 suppresses human fibroblasts-induced metastasis of clear cell renal cell carcinoma via an anti-IL6/STAT3 mechanism

CXXC5: A novel regulator and coordinator of TGF‐β, BMP and Wnt signaling

Contact Info

Product

Resources

About