DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling.
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.
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
D W
DW
Chan
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
W W Y
WW
Hui
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China.|Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
J J
JJ
Wang
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
M M H
MM
Yung
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
L M N
LM
Hui
Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Y
Y
Qin
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
R R
RR
Liang
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
T H Y
TH
Leung
Department of Medical Laboratory Science, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Hudson Institute of Medical Research, Clayton, Victoria, Australia.
D
D
Xu
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
K K L
KK
Chan
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China.
K-M
KM
Yao
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.|Departments of Obstetrics and Gynaecology, and Cellular and Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada.|Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
B K
BK
Tsang
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong SAR, China.
H Y S
HY
Ngan
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000378:metabolism*; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D059372:Nucleotide Motifs; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C088334:Distal-less homeobox proteins; D000072278:Forkhead Box Protein M1; D018398:Homeodomain Proteins; D051901:Smad4 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta