Ski regulates Smads and TAZ signaling to suppress lung cancer progression

Wu, Xiaojun; Zhang, Jinjun; Zhang, Jiexia; Li, Xiangxiang

doi:10.1002/mc.22661

Cited by 19 publications

(16 citation statements)

References 46 publications

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“… 97 – 100 Recently, it has been reported that the Ski gene is hypermethylated and silenced in human primary lung cancer tissues, supporting Ski function as a tumor suppressor. 101 Ski mRNA levels are also modulated by different miRNAs, such as miR-21, miR-29a, miR-155, and miR-127-3p (Fig. 2 ).…”

Section: Ski and Snon Are Major Negative Regulators Of The Tgf-β Signmentioning

confidence: 99%

“…The Ski protein interacts with Lats2 and enhances its activity to destabilize the TAZ protein in mammary epithelial cells, 69 whereas, in lung cancer, the Ski gene is silenced by methylation and, consequently, Ski is unable to inhibit TAZ. 101 Ski and SnoN negatively regulate the expression of the Indian hedgehog ( Ihh ) gene in primary chondrocytes via different transcriptional complexes: SnoN/Smad2 and HDAC4 form a complex with high affinity; whereas, the Ski/Smad3 complex has a lower affinity. 210 Furthermore, gefitinib is a drug that is used to treat lung cancer; thus, the IL-6 cytokine induces Stat3 phosphorylation to repress Smad3 expression, promoting gefitinib resistance, and Stat3 interacts with Ski and SnoN to inhibit the R-Smad/co-Smad complex.…”

Section: Regulation Of Tgf-β/smad Signaling By Ski and Snonmentioning

confidence: 99%

“…Under this scenario, Ski fails to block TAZ activity and the proliferation of lung cancer cells. 101 Moreover, one of the treatments to regulate Ski protein levels includes the use of the TGF-β inhibitory P144 peptide, which is derived from the extracellular sequence of the human TGF-β type III receptor, and interestingly, P144 promotes Ski downregulation in human glioblastoma cell lines, such as A172 and U-87 MG. 286 …”

Section: Regulation Of Tgf-β/smad Signaling By Ski and Snonmentioning

confidence: 99%

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Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Tecalco-Cruz

Ríos-López

Vázquez‐Victorio

et al. 2018

Sig Transduct Target Ther

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The transforming growth factor-β (TGF-β) family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis. The TGF-β signaling pathway outcome relies on the control of the spatial and temporal expression of >500 genes, which depend on the functions of the Smad protein along with those of diverse modulators of this signaling pathway, such as transcriptional factors and cofactors. Ski (Sloan-Kettering Institute) and SnoN (Ski novel) are Smad-interacting proteins that negatively regulate the TGF-β signaling pathway by disrupting the formation of R-Smad/Smad4 complexes, as well as by inhibiting Smad association with the p300/CBP coactivators. The Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone deacetylases to repress gene transcription. The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms. Thus, these cross-regulatory processes finely modify the TGF-β signaling outcome as they control the magnitude and duration of the TGF-β signals. As a result, any alteration in these regulatory mechanisms may lead to disease development. Therefore, the design of targeted therapies to exert tight control of the levels of negative modulators of the TGF-β pathway, such as Ski and SnoN, is critical to restore cell homeostasis under the specific pathological conditions in which these cofactors are deregulated, such as fibrosis and cancer.

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Section: Ski and Snon Are Major Negative Regulators Of The Tgf-β Signmentioning

confidence: 99%

Section: Regulation Of Tgf-β/smad Signaling By Ski and Snonmentioning

confidence: 99%

Section: Regulation Of Tgf-β/smad Signaling By Ski and Snonmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Tecalco-Cruz

Ríos-López

Vázquez‐Victorio

et al. 2018

Sig Transduct Target Ther

View full text Add to dashboard Cite

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“…A recent study found that Ski inhibits YAP and mainly TAZ in lung because it induces their phosphorylation mediated by LATS1/2, thus inducing their proteasome-mediated degradation but not their cytoplasmic translocation. In 56% of NSCLC tissues, the Ski promoter is hypermethylated and its downregulation is associated with poorer prognosis [ 130 ].…”

Section: Hippo Pathway In Lung Cancermentioning

confidence: 99%

YAP and TAZ in Lung Cancer: Oncogenic Role and Clinical Targeting

Sardo¹,

Strano²,

Blandino³

2018

Cancers

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Lung cancer is the leading cause of cancer death in the world and there is no current treatment able to efficiently treat the disease as the tumor is often diagnosed at an advanced stage. Moreover, cancer cells are often resistant or acquire resistance to the treatment. Further knowledge of the mechanisms driving lung tumorigenesis, aggressiveness, metastasization, and resistance to treatments could provide new tools for detecting the disease at an earlier stage and for a better response to therapy. In this scenario, Yes Associated Protein (YAP) and Trascriptional Coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as promising therapeutic targets. Here, we will discuss the most recent advances made in YAP and TAZ biology in lung cancer and, more importantly, on the newly discovered mechanisms of YAP and TAZ inhibition in lung cancer as well as their clinical implications.

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“…We carried out BioID2 analyses to address novel mechanisms by which SKI interacts, and potentially regulates, Hippo signaling in primary cardiac fibroblasts. Previous oncological studies suggest that SKI interacts with several core Hippo pathway components, including LATS2; however, they utilized cancer cell lines (i.e., breast, kidney, and lung) [40,58]. They revealed a decrease in TAZ protein expression with ectopic SKI expression, as well as a marked reduction in cell proliferation, migration, and tumorigenicity.…”

Section: Discussionmentioning

confidence: 97%

SKI activates the Hippo pathway via LIMD1 to inhibit cardiac fibroblast activation

et al. 2021

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We have previously shown that overexpression of SKI, an endogenous TGF-β1 repressor, deactivates the pro-fibrotic myofibroblast phenotype in the heart. We now show that SKI also functions independently of SMAD/TGF-β signaling, by activating the Hippo tumor-suppressor pathway and inhibiting the Transcriptional co-Activator with PDZ-binding motif (TAZ or WWTR1). The mechanism(s) by which SKI targets TAZ to inhibit cardiac fibroblast activation and fibrogenesis remain undefined. A rat model of post-myocardial infarction was used to examine the expression of TAZ during acute fibrogenesis and chronic heart failure. Results were then corroborated with primary rat cardiac fibroblast cell culture performed both on plastic and on inert elastic substrates, along with the use of siRNA and adenoviral expression vectors for active forms of SKI, YAP, and TAZ. Gene expression was examined by qPCR and luciferase assays, while protein expression was examined by immunoblotting and fluorescence microscopy. Cell phenotype was further assessed by functional assays. Finally, to elucidate SKI’s effects on Hippo signaling, the SKI and TAZ interactomes were captured in human cardiac fibroblasts using BioID2 and mass spectrometry. Potential interactors were investigated in vitro to reveal novel mechanisms of action for SKI. In vitro assays on elastic substrates revealed the ability of TAZ to overcome environmental stimuli and induce the activation of hypersynthetic cardiac myofibroblasts. Further cell-based assays demonstrated that SKI causes specific proteasomal degradation of TAZ, but not YAP, and shifts actin cytoskeleton dynamics to inhibit myofibroblast activation. These findings were supported by identifying the bi-phasic expression of TAZ in vivo during post-MI remodeling and fibrosis. BioID2-based interactomics in human cardiac fibroblasts suggest that SKI interacts with actin-modifying proteins and with LIM Domain-containing protein 1 (LIMD1), a negative regulator of Hippo signaling. Furthermore, we found that LATS2 interacts with TAZ, whereas LATS1 does not, and that LATS2 knockdown prevented TAZ downregulation with SKI overexpression. Our findings indicate that SKI’s capacity to regulate cardiac fibroblast activation is mediated, in part, by Hippo signaling. We postulate that the interaction between SKI and TAZ in cardiac fibroblasts is arbitrated by LIMD1, an important intermediary in focal adhesion-associated signaling pathways. This study contributes to the understanding of the unique physiology of cardiac fibroblasts, and of the relationship between SKI expression and cell phenotype.

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Ski regulates Smads and TAZ signaling to suppress lung cancer progression

Cited by 19 publications

References 46 publications

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

YAP and TAZ in Lung Cancer: Oncogenic Role and Clinical Targeting

SKI activates the Hippo pathway via LIMD1 to inhibit cardiac fibroblast activation

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