KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling
Abstract
:1. SP/KLF Family
2. KLF10 Induced Mechanism of Gene Activation
3. KLF10 Role in Various Diseases
3.1. Diabetes
3.2. Bone Disease
3.3. Heart Hypertrophy
3.4. Other Diseases
3.5. Phenotype in KLF10 Deficient Models
4. Role of KLF10 as a Tumor Suppressor in Various Cancers
4.1. Liver Cancer
4.2. Pancreatic Cancer
4.3. Lung Cancer
4.4. Breast Cancer
4.5. Colon Cancer
4.6. Human Prostate Cancer
4.7. Metastatic Brain Tumors
4.8. Renal Cancer
4.9. Other Cancers
5. Concluding Remarks
Acknowledgments
Conflicts of Interest
References
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Name | Previous Name | Transcription Activity | Expression Pattern | Disease | TGFβ Signaling |
---|---|---|---|---|---|
Sp1 | TFSP1 | Activator | Ubiquitous | Alzheimer’s disease (AD) | Co-activator of Smad-dependent transduction pathway in AD |
Sp2 | KIAA0048 | Activator/Repressor | Unknown | Unknown | Unknown |
Sp3 | SPR-2 | Activator/Repressor | Ubiquitous | Pathogenesis of keratoconus | SP1/Sp3 activities control TGFβRII gene |
Sp4 | SPR-1, HF1B | Activator/Repressor | Brain enriched | Unknown | Unknown |
Sp5 | Unknown | Ubiquitous | Unknown | Unknown | |
Sp6 | Activator | Ubiquitous | Unknown | Unknown | |
Sp7 | OSX | Unknown | Osteoblastic cells | Bone cell differentiation | Unknown |
Sp8 | BTD | Unknown | Neurogenic regions | Neural tube formation | Unknown |
Sp9 | ZNF990 | Unknown | Unknown | Unknown | Embryonic limb morphogenesis |
KLF1 | E-KLF | Activator | Erythropoietic tissues (fetal liver and adult bone marrow) | Anemia β-thalassemia | Unknown |
KLF2 | L-KLF | Activator | Ubiquitous | Glomerular disease, atherosclerosis, vascular inflammation, cancers (leukemia, breast, colon, intestine, prostate) | Inhibits TGF-β signaling in atherosclerosis |
KLF3 | BKLF, TEF-2 | Activator/Repressor | Ubiquitous | Cancer (leukemia, cervix) | Unknown |
KLF4 | G-KLF, EZF | Activator/Repressor | Ubiquitous | Glomerular disease, IBD, acute kidney injury, liver fibrosis, heart failure, axon regeneration, different types of cancers (bladder, brain, breast, cervix, colon, intestine, esophagus, head and neck, liver, leukemia, lung, lymphoma, prostate, skin stomach, melanoma, pancreas) | Cell proliferation and differentiation, important target in macrophages |
KLF5 | I-KLF, C-KLF, BTEB2 | Activator/Repressor | Gut and epithelial tissue, Placenta | IBD, kidney fibrosis, different types of cancers (leukemia, breast, colon, intestine, esophagus, head and neck, gastrointestinal stromal tumor, lung) pancreas, melanoma, prostate, stomach) | Proliferation, TGFβ induced growth arrest |
KLF6 | BCD1, COPEB, CPBP, GBF, PAC1, ST12, Zf9 | Activator | Ubiquitous | Cardiac fibrosis, kidney fibrosis, different types of cancers (leukemia, bone, breast, brain, colon, intestine, head and neck, liver, lung, ovary, pancreas, pituitary, prostate, stomach) | Cell proliferation in skeletal myoblasts |
KLF7 | U-KLF | Activator | Ubiquitous | Type 2 diabetes | Satellite cell quiescence |
KLF8 | BKLF3, ZNF741 | Repressor | Ubiquitous | Cancers (breast, kidney, liver, ovary, prostate, stomach) | EMT |
KLF9 | BTEB, BTEB1 | Activator | Ubiquitous | Demyelinating disorders, different types of cancers (brain, colon, intestine, multiple myeloma, uterus) | Thyroid hormone regulation |
KLF10 | TIEG, TIEG1, EGRα | Activator/Repressor | Ubiquitous | Angiogenesis, cardiac hypertrophy, different types of cancers (breast, kidney, pancreas, prostate) | TGFβ induced growth inhibition |
KLF11 | F-KLF, TIEG2, MODY7 | Activator/Repressor | Ubiquitous | Liver fibrosis, type 2 diabetes, different types of cancers (leukemia, breast, colon, intestine, kidney, lung, ovary, pancreas, stomach) | TGFβ induced growth inhibition |
KLF12 | AP-2rep, AP2REP, HSPC122 | Repressor | Brain, kidney, liver, lung | Head and neck cancer, stomach progression of gastric cancer, salivary gland tumors, autosomal dominant polycystic kidney disease (ADPKD) | Unknown |
KLF13 | BTEB3, NSLP1, RFLAT-1 | Activator/Repressor | Ubiquitous | Head and neck Cancer | Unknown |
KLF14 | BTEB5, SP6, EPFN | Activator/Repressor | Ubiquitous | Type 2 diabetes | Transcription of TGFβRII |
KLF15 | K-KLF | Repressor | Ubiquitous | Glomerular disease, cardiovascular disease, kidney fibrosis | Cardiac fibrosis |
KLF16 | BTEB4, NSLP2, DRRF | Repressor | Ubiquitous | Adipose tissue expansion | Growth control mechanisms in NHK cells |
KLF17 | ZNF393 | Repressor | Testis, brain, and bone | Cancers (metastasis in breast cancer, lung, hepatocellular carcinoma (HCC), gastric cancer, papillary thyroid carcinoma) | Downstream mediator of the TGF-β signaling pathway, anti-metastasis |
KLF18 | Unknown | Unknown | Unknown | Unknown | Unknown |
Disease | TGFβ Signaling | Comments | Reference |
---|---|---|---|
Bone diseases | RANKL RUNX2 Smad2 ↓ Smad7 ↑ | Osteopenia: KLF10plays a critical role in osteoblast-mediated mineralization and osteoblast support of osteoclast differentiation | [34] |
TGF-β1, BMP2, EGF | Osteoblast: KLF10 plays an active role in mediating Runx2 responses following TGFβ1 and BMP2. | [35] | |
Type 2 diabetes | KLF10, smad7 (weakly contributes) | KLF10 variants make minor contributions to a particular genetic background that increases susceptibility to the development of T2D. | [36] |
Hypertrophy | Pttg1 ↑ (via Sp1 binding sites) | KLF10−/− mice develop a cardiac hypertrophic phenotype with asymmetric hypertrophy, interstitial fibrosis, and myocyte disarray. | [37] |
Immune system | TGF-β1 and Foxp3 ↑ | Loss of KLF10 enhanced CD4+ CD25 T cell activity, which stimulated inflammation and atherosclerosis and increased peripheral proinflammatory cytokines | [38] |
Wound healing | Smad 7 ↑ Smad 2, 3 ↓ | KLF10−/− mice delay wound healing. KLF10 may play a role in dermal wound healing via the TGFβ/Smad pathway. | [39] |
NASH | TGFβ ↑ ChREBP ↓ | Expression of KLF10 significantly increases in diet-induced NASH and ECM producing activated HSCs. | [40] |
Colitis | KLF10, smad2, TGFβRII ↓ | KLF10 regulates TGFβRII expression in murine macrophages via histone H3 modification. | [41] |
Hyperglycemia | KLF10, Pgc-1α, Blood glucose ↑ | KLF10 is an important regulator of hepatic glucose metabolism in mice. | [42] |
Cancer Type | Role | Comments | TGFβ Signaling | Reference |
---|---|---|---|---|
Prostate cancer | Suppressor | Doxazosin-mediated apoptosis in prostate cancer cells involves activation of KLF10 and Smad4 mRNA levels, as well as a decrease in Smad7 mRNA expression | Smad dependent pathway | [71] |
Colorectal cancer | Suppressor | KLF10 is one of the members of the signal transduction of PPARγ pathway | Bcl2 | [72] |
Breast cancer | Suppressor | KLF10 plays an inhibitory role in the proliferation of breast cancer. KLF10 and Smad7 in breast cancers are inversely correlated | Smad7 ↑,KLF10, Smad2, and Bard1 ↓ | [73] |
Lymphoma cells | Suppressor | The participation of Smads in TGFβ induced apoptosis is supported by the increased expression of KLF10, which can activate the mitochondrial apoptotic pathway by increasing the intracellular level of ROS | KLF10 ↑Smad 2,3 ↓ | [74] |
Brain cancer | Suppressor | KLF10 is involved in apoptosis and was expressed at low levels in metastatic brain tumors. | Transactivator of TGFβ | [75] |
Leukemia cells | Suppressor | KLF10 promotes apoptosis through the mitochondrial apoptotic pathway. | BimBax ↑Bcl2, Bcl-xl ↓ | [31] |
Renal cell carcinoma | Suppressor | KLF10 up-regulates the expression of TGFβI in von Hippel-Lindau gene (VHL) deficient tumors. KLF10 is a target of VHL | TGFβ1 ↑ | [76] |
Pancreatic cancer | Suppressor | Overexpression of KLF10 induced by the lentivirus system inhibited pancreatic cancer cell growth in vitro and in vivo. | G1-phase arrest in vitro | [77] |
Activator | Mutational screening of KLF10 in 22 pancreatic cancer cell lines revealed no alterations in expression. | No change in KLF10 expression | [78] | |
Hepatocellular carcinoma (HCC) | Suppressor | Upregulation of KLF10 in the HCC cell line induces inhibition of cellular proliferation | Smad3 Smad 7 | [79] |
Activator | Deficiency of KLF10 suppresses cellular proliferation of hepatocytes during liver tumorigenesis through the TGF-β/Smad pathway | Smad 3 TGFβ1, TGFβ R1 ↑ | [80] | |
Ovarian cancer | Suppressor | KLF10 displays strong BMAL1-dependent circadian expression; the KLF10 promoter recruits BMAL1 and is transactivated by the CLOCK/BMAL1 dimer through a conserved E-box response element. | An interruption in Circadian genes | [81] |
Non–small cell lung carcinoma (NSCLC) | Suppressor | KLF10 suppresses TGFβ-induced EMT in conjunction with SNAI2 and HDAC1. | KLF10 ↓ SNAI1 ↑TGFβ/SMAD signaling ↑ | [82] |
Skin | Suppressor | Loss of KLF10 leads to enhanced tumor formation and progression. | P21 ↑ transcriptional activation in a p53 independent manner. | [83] |
Multiple myelomas | Suppressor | MicroRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activation of the PTEN/PI3K/AKT pathway in multiple myeloma. | PTEN/PI3K/AKT pathway | [42] |
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Memon, A.; Lee, W.K. KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling. Cancers 2018, 10, 161. https://doi.org/10.3390/cancers10060161
Memon A, Lee WK. KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling. Cancers. 2018; 10(6):161. https://doi.org/10.3390/cancers10060161
Chicago/Turabian StyleMemon, Azra, and Woon Kyu Lee. 2018. "KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling" Cancers 10, no. 6: 161. https://doi.org/10.3390/cancers10060161