KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling

Abstract

Krüppel-like factor 10 (KLF10), originally named TGF-β (Transforming growth factor beta) inducible early gene 1 (TIEG1), is a DNA-binding transcriptional regulator containing a triple C2H2 zinc finger domain. By binding to Sp1 (specificity protein 1) sites on the DNA and interactions with other regulatory transcription factors, KLF10 encourages and suppresses the expression of multiple genes in many cell types. Many studies have investigated its signaling cascade, but other than the TGF-β/Smad signaling pathway, these are still not clear. KLF10 plays a role in proliferation, differentiation as well as apoptosis, just like other members of the SP (specificity proteins)/KLF (Krüppel-like Factors). Recently, several studies reported that KLF10 KO (Knock out) is associated with defects in cell and organs such as osteopenia, abnormal tendon or cardiac hypertrophy. Since KLF10 was first discovered, several studies have defined its role in cancer as a tumor suppressor. KLF10 demonstrate anti-proliferative effects and induce apoptosis in various carcinoma cells including pancreatic cancer, leukemia, and osteoporosis. Collectively, these data indicate that KLF10 plays a significant role in various biological processes and diseases, but its role in cancer is still unclear. Therefore, this review was conducted to describe and discuss the role and function of KLF10 in diseases, including cancer, with a special emphasis on its signaling with TGF-β.

Keywords: KLF10; TGF-β; cancer; disease; tumor suppressor.

Figure 1

Phylogenic tree, common structure and zinc finger motif in SP (specificity proteins)/KLF (Krüppel-like Factors) family. (a) Phylogenic analysis based on human protein sequence from NCBI. (b) Structure of KLF family, KLFs isoforms can be divided into 3 groups based on the interaction of their N-terminal site with other proteins for transcriptional co-activators and co-repressors. Group 1 includes KLFs that contain the CtBP binding site. Group 2 includes KLFs that contain the Sin3A interaction domain. Group 3 includes KLFs that interact with acetyl-transferases. KLF15, KLF17, and KLF18 are not included in any of these groups because little is known about their protein interaction motifs and (c) multiple alignments of zinc finger domain of all family members of human Sp/KLF factors. Each protein contains three zinc fingers motifs at the C-terminus, two conserved cysteine residues and two conserved histidine residues for zinc binding are highlighted.

Figure 1

Phylogenic tree, common structure and zinc finger motif in SP (specificity proteins)/KLF (Krüppel-like Factors) family. (a) Phylogenic analysis based on human protein sequence from NCBI. (b) Structure of KLF family, KLFs isoforms can be divided into 3 groups based on the interaction of their N-terminal site with other proteins for transcriptional co-activators and co-repressors. Group 1 includes KLFs that contain the CtBP binding site. Group 2 includes KLFs that contain the Sin3A interaction domain. Group 3 includes KLFs that interact with acetyl-transferases. KLF15, KLF17, and KLF18 are not included in any of these groups because little is known about their protein interaction motifs and (c) multiple alignments of zinc finger domain of all family members of human Sp/KLF factors. Each protein contains three zinc fingers motifs at the C-terminus, two conserved cysteine residues and two conserved histidine residues for zinc binding are highlighted.

Figure 2

TGF-β signaling and its target disease mediated by KLF10 gene. In response to TGFβ ligand binding, KLF10 gene expression is induced in a Smad dependent manner and play a role as a tumor suppressor in many cancers. TGFβ signaling occurs through TGFβ receptors (TβRI and TβRII). Binding of TGFβ ligand to TβRII facilitates phosphorylation of TβRI, which in turn phosphorylates the SMAD2 and SMAD3 proteins. After phosphorylationSmad2/Smad3 form complex with Smad4, and translocate to the nucleus to induce expression of KLF10. Subsequently, KLF10 bind to the promoters of Smad2, Smad7, and TGF-beta1, whereas the expression of the inhibitory Smad7 is blocked to disrupt the negative feedback loop. Importantly, KLF10 serves as a positive feedback loop for regulating TGFβ signaling by inducing the expression of SMAD2 and inhibiting the expression of the inhibitory SMAD7 gene in many cancers.