FOXD1 and Gal-3 Form a Positive Regulatory Loop to Regulate Lung Cancer Aggressiveness

Abstract

Dysregulation of forkhead box D1 (FOXD1) is known to promote tumor progression; however, its molecular mechanism of action is unclear. Based on microarray analysis, we identified galectin-3/LGALS3 (Gal-3) as a potential downstream target of FOXD1, as FOXD1 transactivated Gal-3 by interacting with the Gal-3 promoter to upregulate Gal-3 in FOXD1-overexpressing CL1-0 lung cancer cells. Ectopic expression of FOXD1 increased the expression of Gal-3 and the growth and motility of lung cancer cells, whereas depletion of Gal-3 attenuated FOXD1-mediated tumorigenesis. ERK1/2 interacted with FOXD1 in the cytosol and translocated FOXD1 into the nucleus to activate Gal-3. Gal-3 in turn upregulated FOXD1 via the transcription factor proto-oncogene 1 (ETS-1) to transactivate FOXD1. The increase in ETS-1/FOXD1 expression by Gal-3 was through Gal-3-mediated integrin-β1 (ITGβ1) signaling. The overexpression of both FOXD1 and Gal-3 form a positive regulatory loop to promote lung cancer aggressiveness. Moreover, both FOXD1 and Gal-3 were positively correlated in human lung cancer tissues. Our findings demonstrated that FOXD1 and Gal-3 form a positive feedback loop in lung cancer, and interference of this loop may serve as an effective therapeutic target for the treatment of lung cancers, particularly those related to dysregulation of Gal-3.

Increased expression of FOXD1 is associated with cervical node metastasis and unfavorable prognosis in oral squamous cell carcinoma

“…FOXD1 is also a determinant for the self‐renewal and tumorigenicity of mesenchymal glioma stem cells by combined with ALDH1A3 25 . In particular, pharmacological inhibition or gene knockout of FOXD1 significantly inhibited tumor cell proliferation, invasion and metastasis, stem cell maintenance, and promoting apoptosis both in vitro and in vivo 24‐26 . In summary, FOXD1 can serve as a potential biomarker and a valuable and predictable therapeutic target.…”

“…From molecular level, it has demonstrated that FOXD1 regulates lung cancer aggressiveness by forming a positive feedback loop with Gal3 23 and influences aggressiveness and metastasis via indirect regulation of MMP9 and RAC1B alternative splicing in melanoma cells 21 . FOXD1 is also a determinant for the self‐renewal and tumorigenicity of mesenchymal glioma stem cells by combined with ALDH1A3 25 . In particular, pharmacological inhibition or gene knockout of FOXD1 significantly inhibited tumor cell proliferation, invasion and metastasis, stem cell maintenance, and promoting apoptosis both in vitro and in vivo 24‐26 .…”

FOXD1 Repression Potentiates Radiation Effectiveness by Downregulating G3BP2 Expression and Promoting the Activation of TXNIP-Related Pathways in Oral Cancer

“…Recent reports indicated that FOXD1 plays a oncogenic effect in several types of cancer [ 30 , 31 , 32 , 33 , 34 , 35 , 36 ] and likely associates with the mechanism for radioresistance [ 37 ]. In this study, our data showed that FOXD1 is capable of directly regulating the expression of G3BP2 , which is capable of inhibiting p53 activity through a direct binding, which may further promote p53 nuclear export via increasing p53 sumoylation [ 38 ] and serves as a poor prognostic marker in prostate cancer patients [ 39 ].…”

LncRNA OIP5-AS1 promotes the malignancy of pancreatic ductal adenocarcinoma via regulating miR-429/FOXD1/ERK pathway

“…Present study identified FOXD1 as a target of miR-429. FOXD1, located at chromosome 5q12, is a newly discovered member of the FOX transcription factor family [ 43 ] and acts as a tumor facilitator in various cancers [ 33 , 44 , 45 ]. Currently, we discovered that FOXD1 interacted with miR-429 and was positively regulated by OIP5-AS1.…”