SOX9 inhibits β-TrCP-mediated protein degradation to promote nuclear GLI1 expression and cancer stem cell properties

Deng, Wentao; Vanderbilt, Daniel B.; Lin, Chen-Chung; Martin, Karen H.; Brundage, Kathleen M.; Ruppert, J. Michael

doi:10.1242/jcs.162164

Cited by 47 publications

(42 citation statements)

References 76 publications

(130 reference statements)

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“…SOX9 also contributes to the maintenance of stem/progenitor cells in the liver, pancreas, and hair follicles (Furuyama et al, 2011, Vidal et al, 2005). Consequently, dysregulated SOX9 expression has been linked to the initiation and growth of a wide range of tumors: it has been shown to enhance proliferation and migration of prostate cancer cells and the formation of pancreatic ductal adenocarcinomas and is also implicated in metastasis and endocrine resistance in breast cancer (Deng et al, 2015, Jeselsohn et al, 2017). In murine BCCs, SOX9 was recently shown to be required for tumor initiation in a Wnt/β-catenin-dependent manner (Larsimont et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas

Kim

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Chaudhary

et al. 2018

Journal of Investigative Dermatology

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Currently available SMO targeted therapies in patients with basal cell nevus syndrome (BCNS) are associated with substantial tumor recurrence and clinical resistance. Strategies bypassing SMO and/or identifying additional downstream components of the Hedgehog (Hh) pathway could provide novel anti-tumor targets with a better therapeutic index. SOX9 is a Hh/GLI-regulated transcription factor known to be overexpressed in BCCs. A sequence motif search for SOX9-responsive elements identified three motifs in the promoter region of mTOR. In murine BCC cells, SOX9 occupies the mTOR promoter and induces its transcriptional activity. shRNA-mediated knockdown of SOX9, as well as SMO inhibition by itraconazole and vismodegib, reduces mTOR expression and the phosphorylation of known downstream mTOR targets. These effects culminate in diminishing the proliferative capacity of BCC cells, demonstrating a direct mechanistic link between the Hh and mTOR pathways capable of driving BCC growth. Furthermore, rapamycin, a pharmacologic mTOR inhibitor, suppressed growth of UV-induced BCCs in Ptch1+/−/SKH-1 mice, a model that closely mimics the accelerated BCC growth pattern of patients with BCNS. Our data demonstrate that Hh signaling converges on mTOR via SOX9, and highlight the SOX9–mTOR axis as a viable additional target downstream of SMO that could enhance tumor elimination in BCC patients.

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Section: Discussionmentioning

confidence: 99%

SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas

Kim

Back

Chaudhary

et al. 2018

Journal of Investigative Dermatology

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“…The stem cell biomarkers CD133, ALDH-1 as well as SHH and its downstream effector Gli-1 are involved in cancer stem cell self-renewal, clonogenicity, tumorigenicity, metastasis and drug resistance of numerous solid cancers, including PDAC [36–38, 50]. Gli-1 additionally stimulates SOX9 transcription [51], which provides an explanation for the observed significant increase of SOX9 in tumor cells. The GABA-induced reduction in the expression of CD133, ALD-1, SHH, Gli-1 and SOX9 thus suggests significant inhibitory effects of GABA on cancer stem cells as contributing factors to the observed PDAC prevention in the current study.…”

Section: Discussionmentioning

confidence: 99%

Prevention of pancreatic cancer in a hamster model by cAMP decrease

et al. 2016

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Smoking and alcoholism are risk factors for the development of pancreatitis-associated pancreatic ductal adenocarcinoma (PDAC). We have previously shown that these cancers overexpressed stress neurotransmitters and cyclic adenosine monophosphate (cAMP) while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was suppressed. Using a hamster model, the current study has tested the hypothesis that cAMP decrease by GABA supplementation in the drinking water prevents the development of pancreatitis-associated PDAC. Our data reveal strong preventive effects of GABA supplementation on the development of PDAC and pancreatic intraductal neoplasia (PanIN). ELISA assays and immunohistochemistry revealed significant decreases in the levels of cAMP and interleukin 6 accompanied by reductions in the expression of several cancer stem cell markers and phosphorylated signaling proteins, which stimulate cell proliferation, and migration in pancreatic exocrine cells of GABA treated animals. We conclude that cAMP decrease by GABA supplementation inhibits multiple cancer stimulating pathways in cancer stem cells, differentiated cancer cells and the immune system, identifying this approach as promising novel tool for the prevention of PDAC in individuals with a history of smoking and alcoholism.

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“…Two-dimensional cell growth was tested on 96-well plates in biological triplicate using ATPlite Luminescence Assay System (Perkin Elmer Inc., Bridgeville, PA) following manufacturer's instructions. Anchorageindependent cell growth (Soft Agar Assay) was performed on 6-well plates in biological triplicates as described (57).…”

Section: D Cell Growth Assay Soft Agar Assay and Wound Healing Assaymentioning

confidence: 99%

WNT1 Inducible Signaling Pathway Protein 1 (WISP1) stimulates melanoma cell invasion and metastasis by promoting epithelial – mesenchymal transition

Deng

Fernández

McLaughlin

et al. 2018

Preprint

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Besides intrinsic changes, malignant cells release soluble signals to reshape their microenvironment. Among the signaling factors is WNT1 inducible signaling pathway protein 1 (WISP1), a secreted matricellular protein that is elevated in a variety of cancers including melanoma and is associated with reduced overall survival of patients diagnosed with primary melanoma. In this work, we found that WISP1 knockout both increased cell proliferation and repressed wound healing, migration and invasion of mouse and human melanoma cells in an ensemble of in vitro assays. In vivo metastasis assays showed that WISP1 knockout repressed tumor metastasis in both C57BL/6Ncrl and NODscid IL2Rgammanull (NSG) mice with B16F10 and YUMM1.7 melanoma cells. Mechanistically, B16F10 cells that invaded in a transwell assay possessed a gene expression signature similar to Epithelial -Mesenchymal Transition (EMT), including coincident repression of E-cadherin and induction of fibronectin and N-cadherin. Upon WISP1 knockout, these EMT signature genes went in opposite directions in both mouse and human cell lines and were rescued by media containing WISP1 or recombinant WISP1 protein. In vivo, metastasis repression by WISP1 knockout was reversed by the reintroduction of either WISP1 or SNAI1. A set of EMT gene activation and inhibition experiments using recombinant WISP1 or kinase inhibitors in B16F10 and YUMM1.7 cells suggested that WISP1 activates Akt and MAP kinase signaling pathways to shift melanoma cells from a proliferative to invasive phenotype. Collectively, the results supported a model that WISP1 within the tumor microenvironment stimulates melanoma invasion and metastasis by promoting an EMT-like process.

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SOX9 inhibits β-TrCP-mediated protein degradation to promote nuclear GLI1 expression and cancer stem cell properties

Cited by 47 publications

References 76 publications

SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas

SOX9 Transcriptionally Regulates mTOR-Induced Proliferation of Basal Cell Carcinomas

Prevention of pancreatic cancer in a hamster model by cAMP decrease

WNT1 Inducible Signaling Pathway Protein 1 (WISP1) stimulates melanoma cell invasion and metastasis by promoting epithelial – mesenchymal transition

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