ZEB2–Sp1 cooperation induces invasion by upregulating cadherin-11 and integrin α5 expression

Nam, Eun-Hee; Lee, Yunhee; Zhao, Xue-Feng; Park, Young-Kyu; Lee, Sang Eun; Kim, Semi

doi:10.1093/carcin/bgt340

Cited by 46 publications

(45 citation statements)

References 37 publications

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“…In addition, the Gas6/Axl pathway upregulates Slug expression through MAPK [29, 51], suggesting a positive feedback loop between Slug and Axl during cancer progression. On the other hand, we previously reported that ZEB2 directly interacts/cooperates with Sp1 to function as a transcriptional activator of mesenchymal genes (vimentin, integrin α5, and cadherin-11) to induce invasion [53]. We also found that functional cooperation between Twist1 and AP-1 induces EMT and invasion [54].…”

Section: Discussionmentioning

confidence: 98%

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

Lee

Min

et al. 2016

Oncotarget

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TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, and metastasis. We also found that TMPRSS4 activates the transcription factor activating protein-1 (AP-1) to induce cancer cell invasion. Here, we explored TMPRSS4-mediated cellular functions and the underlying mechanisms. TMPRSS4 induced Slug, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, and cyclin D1 through activation of AP-1, composed of c-Jun and activating transcription factor (ATF)-2, which resulted in enhanced invasion and proliferation of PC3 prostate cancer cells. In PC3 cells, not only c-Jun but also Slug was required for TMPRSS4-mediated proliferation and invasion. Interestingly, Slug induced phosphorylation of c-Jun and ATF-2 to activate AP-1 through upregulation of Axl, establishing a positive feedback loop between Slug and AP-1, and thus induced cyclin D1, leading to enhanced proliferation. Using data from The Cancer Genome Atlas, we found that Slug expression positively correlated with that of c-Jun and cyclin D1 in human prostate cancers. Expression of Slug was positively correlated with that of cyclin D1 in various cancer cell lines, whereas expression of other EMT-inducing transcription factors was not. This study demonstrates that TMPRSS4 modulates both invasion and proliferation via Slug and cyclin D1, which is a previously unrecognized pathway that may regulate metastasis and cancer progression.

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Section: Discussionmentioning

confidence: 98%

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

Lee

Min

et al. 2016

Oncotarget

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“…Given the expression patterns and regulation that we observe, it is possible that ZEB2 directly controls miR-200c . Indeed, although ZEB proteins are thought to act primarily as transcriptional repressors by recruiting co-repressors, such as CtBP 32,33 or NuRD 34–36 , they can also induce gene activation by recruiting co-activators such as the Specificity protein (Sp1) or Yes-associated protein (YAP1) 37–39 . Finally, it remains to be determined whether Zeb1 , which is expressed at very low levels in the VZ of midbrain (present study) and regulates miR-200 family members 3,40 , may crosstalk with the Zeb2-miR-200 loop.…”

Section: Discussionmentioning

confidence: 99%

A Zeb2-miR-200c loop controls midbrain dopaminergic neuron neurogenesis and migration

et al. 2018

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Zeb2 is a homeodomain transcription factor that plays pleiotropic functions during embryogenesis, but its role for midbrain dopaminergic (mDA) neuron development is unknown. Here we report that Zeb2 is highly expressed in progenitor cells in the ventricular zone of the midbrain floor plate and downregulated in postmitotic neuroblasts. Functional experiments show that Zeb2 expression in the embryonic ventral midbrain is dynamically regulated by a negative feedback loop that involves miR-200c. We also find that Zeb2 overexpression reduces the levels of CXCR4, NR4A2, and PITX3 in the developing ventral midbrain in vivo, resulting in migration and mDA differentiation defects. This phenotype was recapitulated by miR-200c knockdown, suggesting that the Zeb2-miR-200c loop prevents the premature differentiation of mDA progenitors into postmitotic cells and their migration. Together, our study establishes Zeb2 and miR-200c as critical regulators that maintain the balance between mDA progenitor proliferation and neurogenesis.

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“…Few studies to date have investigated the regulation of cadherin-11 transcription. However, GSK-3␤ has been implicated in the suppression of cadherin-11 expression (34), whereas the transcription factors ZEB2 and SP-1 have been reported to co-operate in the up-regulation of cadherin-11 expression (35). Interestingly, AP-1 can induce the expression of ZEB2 in breast cancer cells (36), and c-JUN can bind SP-1 in epidermal growth factor-stimulated squamous-cell cancer cells (37).…”

Section: Discussionmentioning

confidence: 99%

AP-1 Transcription Factors c-FOS and c-JUN Mediate GnRH-Induced Cadherin-11 Expression and Trophoblast Cell Invasion

Peng

Zhu

et al. 2015

Endocrinology

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GnRH is expressed in first-trimester human placenta and increases cell invasion in extravillous cytotrophoblasts (EVTs). Invasive phenotypes have been reported to be regulated by transcription factor activator protein 1 (AP-1) and mesenchymal cadherin-11. The aim of our study was to investigate the roles of AP-1 components (c-FOS/c-JUN) and cadherin-11 in GnRH-induced cell invasion in human EVT cells. Phosphorylated c-FOS and phosphorylated c-JUN were detected in the cell column regions of human first-trimester placental villi by immunohistochemistry. GnRH treatment increased c-FOS, c-JUN, and cadherin-11 mRNA and protein levels in immortalized EVT (HTR-8/SVneo) cells. Moreover, GnRH treatment induced c-FOS and c-JUN protein phosphorylation and nuclear accumulation. Pretreatment with antide, a GnRH antagonist, attenuated GnRH-induced cadherin-11 expression. Importantly, basal and GnRH-induced cadherin-11 expression and cell invasion were reduced by small interfering RNA-mediated knockdown of c-FOS, c-JUN, and cadherin-11 in HTR-8/SVneo cells. Our results suggest that GnRH induces the expression and phosphorylation of the AP-1 transcription factors c-FOS and c-JUN in trophoblast cells, which contributes to GnRH-induced elevation of cadherin-11 expression and cell invasion.

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ZEB2–Sp1 cooperation induces invasion by upregulating cadherin-11 and integrin α5 expression

Cited by 46 publications

References 37 publications

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1

A Zeb2-miR-200c loop controls midbrain dopaminergic neuron neurogenesis and migration

AP-1 Transcription Factors c-FOS and c-JUN Mediate GnRH-Induced Cadherin-11 Expression and Trophoblast Cell Invasion

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