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PMID:26416422
| Citation |
Zhang, W, Levi, L, Banerjee, P, Jain, M and Noy, N (2015) Kruppel-like factor 2 suppresses mammary carcinoma growth by regulating retinoic acid signaling. Oncotarget 6:35830-42 |
|---|---|
| Abstract |
The transcription factor Kruppel-like factor 2 (KLF2) displays anticarcinogenic activities but the mechanism that underlies this activity is unknown. We show here that KLF2 is markedly downregulated in human breast cancers and that its expression positively correlates with breast cancer patient survival. We show further that KLF2 suppresses tumor development by controlling the transcriptional activity of the vitamin A metabolite retinoic acid (RA). RA regulates gene transcription by activating two types of nuclear receptors: RA receptors (RARs), which inhibit tumor development, and peroxisome proliferator-activated receptor β/δ (PPARβ/δ), which promotes tumorigenesis. The partitioning of RA between these receptors is regulated by two carrier proteins: cellular retinoic acid-binding protein 2 (CRABP2), which delivers RA to RARs, and fatty acid-binding protein 5 (FABP5), which shuttles ligands to PPARβ/δ. We show that KLF2 induces the expression of CRABP2 and RARγ and inhibits the expression FABP5 and PPARβ/δ thereby shifting RA signaling from the pro-carcinogenic FABP5/PPARβ/δ to the growth-suppressing CRABP2/RAR path. The data thus reveal that KLF2 suppresses tumor growth by controlling the transcriptional activities of RA. |
| Links |
PubMed PMC4742144 Online version:10.18632/oncotarget.5767 |
| Keywords |
Animals; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Cell Line, Tumor; Cell Proliferation/physiology; Cell Transformation, Neoplastic; Down-Regulation; Fatty Acid-Binding Proteins/antagonists & inhibitors; Female; Heterografts; Humans; Kruppel-Like Transcription Factors/genetics; Kruppel-Like Transcription Factors/metabolism; MCF-7 Cells; Mice; Mice, Nude; Receptors, Retinoic Acid/biosynthesis; Receptors, Retinoic Acid/genetics; Signal Transduction; Transcription, Genetic; Tretinoin/metabolism |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0048386: positive regulation of retinoic acid receptor signaling pathway |
ECO:0000314: |
P |
In accordance with activation of RAR and suppression of PPAR-mediated activity by KLF2, analyses of cultured cells (Figure S1F-S1I) and of tumors that arose in NCr mice showed that overexpression of KLF2 upregulated levels of mRNA of the endogenous the RAR target genes BTG2 [26] and CYP26a [46, 47] (Figure 2H). |
complete | ||||
Notes
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References
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