Format

Send to

Choose Destination
Oncogene. 2017 Mar;36(10):1404-1416. doi: 10.1038/onc.2016.307. Epub 2016 Sep 5.

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

Author information

1
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
2
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China.
3
Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
4
Department of Medical Laboratory Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
5
Hudson Institute of Medical Research, Clayton, Victoria, Australia.
6
Macau Institute for Applied Research in Medicine and Health, State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, China.
7
Departments of Obstetrics and Gynaecology, and Cellular and Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada.
8
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.

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.

PMID:
27593933
PMCID:
PMC5348575
DOI:
10.1038/onc.2016.307
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center