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.

• Authors: D W Chan, W W Y Hui, J J Wang, M M H Yung, L M N Hui, Y Qin, R R Liang, T H Y Leung, D Xu, K K L Chan, K-M Yao, B K Tsang, H Y S Ngan
• Journal: Oncogene (Oncogene) Vol. 36 Issue 10 Pg. 1404-1416 (03 2017) ISSN: 1476-5594 [Electronic] England
• PMID: 27593933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Distal-less homeobox proteins
• Forkhead Box Protein M1
• Homeodomain Proteins
• Smad4 Protein
• Transcription Factors
• Transforming Growth Factor beta

Topics

• Animals
• Binding Sites
• Cell Line, Tumor
• Cell Movement (genetics)
• Disease Models, Animal
• Disease Progression
• Female
• Forkhead Box Protein M1 (metabolism)
• Heterografts
• Homeodomain Proteins (genetics)
• Humans
• Mice
• Neoplasm Grading
• Neoplasm Metastasis
• Nucleotide Motifs
• Ovarian Neoplasms (genetics, metabolism, pathology)
• Promoter Regions, Genetic
• Protein Binding
• Signal Transduction
• Smad4 Protein (metabolism)
• Transcription Factors (genetics)
• Transcriptional Activation
• Transforming Growth Factor beta (metabolism)