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

DW Chan, W. W Y Hui, J J Wang, M. M H Yung, LMN Hui, Y Qin, RR Liang, T. H Y Leung, D Xu, KKL Chan, K-M Yao, B. K. Tsang, H. Y S Ngan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Recent 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 transforming growth factor-β (TGF-β) signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-β1 induction. Taken together, these data strongly suggest that DLX1 has a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-β/SMAD4 signaling in high-grade serous ovarian cancer cells.

Original languageEnglish
Pages (from-to)1404-1416
Number of pages13
JournalOncogene
Volume36
Issue number10
DOIs
Publication statusPublished - 1 Mar 2017
Externally publishedYes

Cite this

Chan, DW., Hui, W. W. Y., Wang, J. J., Yung, M. M. H., Hui, LMN., Qin, Y., ... Ngan, H. Y. S. (2017). DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling. Oncogene, 36(10), 1404-1416. https://doi.org/10.1038/onc.2016.307
Chan, DW ; Hui, W. W Y ; Wang, J J ; Yung, M. M H ; Hui, LMN ; Qin, Y ; Liang, RR ; Leung, T. H Y ; Xu, D ; Chan, KKL ; Yao, K-M ; Tsang, B. K. ; Ngan, H. Y S. / DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling. In: Oncogene. 2017 ; Vol. 36, No. 10. pp. 1404-1416.
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title = "DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling",
abstract = "Recent 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 transforming growth factor-β (TGF-β) signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-β1 induction. Taken together, these data strongly suggest that DLX1 has a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-β/SMAD4 signaling in high-grade serous ovarian cancer cells.",
author = "DW Chan and Hui, {W. W Y} and Wang, {J J} and Yung, {M. M H} and LMN Hui and Y Qin and RR Liang and Leung, {T. H Y} and D Xu and KKL Chan and K-M Yao and Tsang, {B. K.} and Ngan, {H. Y S}",
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Chan, DW, Hui, WWY, Wang, JJ, Yung, MMH, Hui, LMN, Qin, Y, Liang, RR, Leung, THY, Xu, D, Chan, KKL, Yao, K-M, Tsang, BK & Ngan, HYS 2017, 'DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling', Oncogene, vol. 36, no. 10, pp. 1404-1416. https://doi.org/10.1038/onc.2016.307

DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling. / Chan, DW; Hui, W. W Y; Wang, J J; Yung, M. M H; Hui, LMN; Qin, Y; Liang, RR; Leung, T. H Y; Xu, D; Chan, KKL; Yao, K-M; Tsang, B. K.; Ngan, H. Y S.

In: Oncogene, Vol. 36, No. 10, 01.03.2017, p. 1404-1416.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling

AU - Chan, DW

AU - Hui, W. W Y

AU - Wang, J J

AU - Yung, M. M H

AU - Hui, LMN

AU - Qin, Y

AU - Liang, RR

AU - Leung, T. H Y

AU - Xu, D

AU - Chan, KKL

AU - Yao, K-M

AU - Tsang, B. K.

AU - Ngan, H. Y S

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Recent 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 transforming growth factor-β (TGF-β) signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-β1 induction. Taken together, these data strongly suggest that DLX1 has a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-β/SMAD4 signaling in high-grade serous ovarian cancer cells.

AB - Recent 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 transforming growth factor-β (TGF-β) signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-β1 induction. Taken together, these data strongly suggest that DLX1 has a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-β/SMAD4 signaling in high-grade serous ovarian cancer cells.

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