Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism

Abstract

TGFβ-SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Krüppel-like transcription factor KLF10 is a pivotal effector of TGFβ/SMAD signaling that mediates anti-proliferative effects of TGFβ. In this study, we show how KLF10 opposes the pro-metastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the anti-proliferative versus pro-metastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression.

circRNA circFUT8 Upregulates Krüpple-like Factor 10 to Inhibit the Metastasis of Bladder Cancer via Sponging miR-570-3p

“…21 KLF10 was also identified as an anti-metastasis gene by the inhibition of Slug gene transcription. 22 In our study, functional assays revealed that KLF10 inhibited the migration and invasion of BCa cell lines ( Figures 6C and 6D).…”

“…Transcript factor KLF10 was characterized as a tumor-suppressor gene in cancers. 21,22 Metastatic brain tumors from lung adenocarcinoma indicated that KLF10 was at an abnormally low level in brain tumors. 21 KLF10 was also identified as an anti-metastasis gene by the inhibition of Slug gene transcription.…”

Extracellular vesicles in urologic malignancies—Implementations for future cancer care

“…It has been shown that tumour cells have a higher propensity to secrete larger quantity of exosome 67,68 ; for instance, cancer-associated fibroblasts (CAFs) support tumour cells in proliferation, delaying senescence and resisting against drugs, which induced by exosome-secreted miR-9 and the human telomerase reverse transcriptase (hTERT). 69,70 Activation of signalling pathways by exosomes is one of the way to modulate the tumour microenvironment, such as irritation of the TGF-β/Smad pathway by transferring TGF-β to human umbilical cord-derived mesenchymal cells (hucMSCs), subsequently differentiating into CAFs. 71 Moreover, recent research shows that transferring TGF-β also contributes fibroblasts converse to myofibroblasts, which could secrete insulin-like growth factor 1 (IGF-1), activin A and VEGF to induce tumour progression.…”

Tanshinone IIA Inhibits Epithelial-to-mesenchymal Transition Through Regulating β-arrestin1 Mediated β-catenin Signaling Pathway in Colorectal Cancer

“…During EMT, down-regulation of E-cadherin leads to the loss of cell adhesion, upregulation of Vimentin and N-cadherin causes the reorganization of the actin cytoskeleton and promotes the motility [5], and upregulation of transcription factors such as Snail, Slug and Twist induces EMT [6]. In addition, TGF-β/SMADs [7], PI3K/Akt [8] and other signaling pathways were participated in regulating EMT. In our previous study, we have found that β-arrestin1 had a higher expression in lung metastases than in primary CRC.…”