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Article: DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling

TitleDLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling
Authors
Issue Date2016
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2016 How to Cite?
AbstractRecent evidence from a comprehensive genome analysis and functional studies have revealed that FOXM1 is a crucial metastatic regulator that drives cancer progression. However, the regulatory mechanism by which FOXM1 exerts its metastatic functions in cancer cells remains obscure. Here, we report that DLX1 acts as a FOXM1 downstream target, exerting pro-metastatic function in ovarian cancers. Both FOXM1 isoforms (FOXM1B or FOXM1C) could transcriptionally upregulate DLX1 through two conserved binding sites, located at +61 to +69bp downstream (TFBS1) and -675 to -667bp upstream (TFBS2) of the DLX1 promoter, respectively. This regulation was further accentuated by the significant correlation between the nuclear expression of FOXM1 and DLX1 in high-grade serous ovarian cancers. Functionally, the ectopic expression of DLX1 promoted ovarian cancer cell growth, cell migration/invasion and intraperitoneal dissemination of ovarian cancer in mice, whereas small interfering RNA-mediated DLX1 knockdown in FOXM1-overexpressing ovarian cancer cells abrogated these oncogenic capacities. In contrast, depletion of FOXM1 by shRNAi only partially attenuated tumor growth and exerted almost no effect on cell migration/invasion and the intraperitoneal dissemination of DLX1-overexpressing ovarian cancer cells. Furthermore, the mechanistic studies showed that DLX1 positively modulates TGF- signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-1 induction. Taken together, these data strongly suggest that DLX1 plays a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-/SMAD4 signaling in high-grade serous ovarian cancer cells.
Persistent Identifierhttp://hdl.handle.net/10722/229672
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047

 

DC FieldValueLanguage
dc.contributor.authorChan, DW-
dc.contributor.authorHui, WW-
dc.contributor.authorWang, JJ-
dc.contributor.authorYung, MH-
dc.contributor.authorHui, MN-
dc.contributor.authorQin, YIMING-
dc.contributor.authorLIANG, R-
dc.contributor.authorLeung, THY-
dc.contributor.authorXu, D-
dc.contributor.authorChan, KKL-
dc.contributor.authorYao, KM-
dc.contributor.authorTsang, BK-
dc.contributor.authorNgan, HYS-
dc.date.accessioned2016-08-23T14:12:34Z-
dc.date.available2016-08-23T14:12:34Z-
dc.date.issued2016-
dc.identifier.citationOncogene, 2016-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/229672-
dc.description.abstractRecent evidence from a comprehensive genome analysis and functional studies have revealed that FOXM1 is a crucial metastatic regulator that drives cancer progression. However, the regulatory mechanism by which FOXM1 exerts its metastatic functions in cancer cells remains obscure. Here, we report that DLX1 acts as a FOXM1 downstream target, exerting pro-metastatic function in ovarian cancers. Both FOXM1 isoforms (FOXM1B or FOXM1C) could transcriptionally upregulate DLX1 through two conserved binding sites, located at +61 to +69bp downstream (TFBS1) and -675 to -667bp upstream (TFBS2) of the DLX1 promoter, respectively. This regulation was further accentuated by the significant correlation between the nuclear expression of FOXM1 and DLX1 in high-grade serous ovarian cancers. Functionally, the ectopic expression of DLX1 promoted ovarian cancer cell growth, cell migration/invasion and intraperitoneal dissemination of ovarian cancer in mice, whereas small interfering RNA-mediated DLX1 knockdown in FOXM1-overexpressing ovarian cancer cells abrogated these oncogenic capacities. In contrast, depletion of FOXM1 by shRNAi only partially attenuated tumor growth and exerted almost no effect on cell migration/invasion and the intraperitoneal dissemination of DLX1-overexpressing ovarian cancer cells. Furthermore, the mechanistic studies showed that DLX1 positively modulates TGF- signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-1 induction. Taken together, these data strongly suggest that DLX1 plays a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-/SMAD4 signaling in high-grade serous ovarian cancer cells.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleDLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling-
dc.typeArticle-
dc.identifier.emailChan, DW: dwchan@hku.hk-
dc.identifier.emailWang, JJ: junwen@hku.hk-
dc.identifier.emailYung, MH: mhyung@hku.hk-
dc.identifier.emailHui, MN: mnhui@hku.hk-
dc.identifier.emailLeung, THY: thyl@hkucc.hku.hk-
dc.identifier.emailChan, KKL: kklchan@hkucc.hku.hk-
dc.identifier.emailYao, KM: kmyao@hku.hk-
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hk-
dc.identifier.authorityChan, DW=rp00543-
dc.identifier.authorityWang, JJ=rp00280-
dc.identifier.authorityChan, KKL=rp00499-
dc.identifier.authorityYao, KM=rp00344-
dc.identifier.authorityNgan, HYS=rp00346-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/onc.2016.307-
dc.identifier.hkuros262164-
dc.publisher.placeUnited Kingdom-

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