Krüppel-Like Factor 8 Is a New Wnt/Beta-Catenin Signaling Target Gene and Regulator in Hepatocellular Carcinoma

Abstract

Krüppel-like factor 8 (KLF8) plays important role in cell cycle and oncogenic transformation. Here we report the mechanisms by which KLF8 crosstalks with Wnt/β-catenin signaling pathway and regulates hepatocellular carcinoma (HCC) cells proliferation. We show that overexpression of KLF8 and nucleus accumulation of β-catenin in the human HCC samples are positively correlated. More importantly, KLF8 protein levels plus nucleus accumulation of β-catenin levels were significantly elevated in high-grade HCC compared to low-grade HCC. Using HCC HepG2 cells we find that, on the one hand both protein and mRNA of KLF8 are up-regulated under Wnt3a stimulation, on the other hand overexpression of KLF8 increases the cytoplasm and nucleus accumulation of β-catenin, recruits p300 to β-catenin/T-cell factor 4 (TCF4) transcription complex, enhances TOP flash report gene transcription, and induces Wnt/β-catenin signaling target genes c-Myc, cyclin D1 and Axin1 expression. Knockdown of KLF8 using shRNA inhibits Wnt3a induced transcription of TOP flash report gene and expression of c-Myc, cyclin D1 and Axin1. Knockdown of β-catenin by shRNA rescues the enhanced HepG2 and Hep3B cells proliferation ability induced by overexpression of KLF8.

Krüppel‐like factor 8 promotes cancer stem cell‐like traits in hepatocellular carcinoma through Wnt/β‐catenin signaling

“…MHCC-LM3 shKLF8 and the control cells were seeded onto 96-well ultralow attachment culture plates at various cell numbers (32,16,8,4,2, and 1 cells per well, n ¼ 8 for each density) and incubated for 7 d. CSC proportions were analyzed using Poisson distribution statistics and the L-Calc Version 1.1 software program (Stem Cell Technologies, Vancouver, Canada).…”

Krüppel-like factor 8 induces epithelial-to-mesenchymal transition and promotes invasion of pancreatic cancer cells through transcriptional activation of four and a half LIM-only protein 2

“…As a GT-box (CACCC) binding dual-transcription factor, KLF8 regulates the transcription of numerous genes by recruiting the C-terminal binding protein (CtBP) corepressor (6-10) or p300 and P300/CtBP-associated factor histone acetyltransferase co-activators (8,(11)(12)(13)(14) in order to target gene promoters. It is aberrantly overexpressed in a number of cancer subtypes and has been implicated in the initiation, development and progression of these cancer subtypes, including hepatocellular carcinoma (15)(16)(17), gastric cancer (18)(19)(20)(21), breast cancer (22,23), ovarian cancer (14,24), renal cancer (22,25) and glioma (26). It is worth noting that KLF8 induced tumor cell epithelial-to-mesenchymal transition (EMT) and maintained the invasive potential of cancer, which appeared to serve a critical role in the metastatic progression of cancer cells (6,27).…”

Generation of Mice Deficient in both KLF3/BKLF and KLF8 Reveals a Genetic Interaction and a Role for These Factors in Embryonic Globin Gene Silencing

“…In addition, KLF8 has been shown to activate transcription from some gene promoters (21)(22)(23)(24). KLF8 is not expressed at readily detectable levels in most cell and tissue types studied to date (55), but numerous studies have reported its upregulation in various human cancers, including prostate (56), gastric (57,58), hepatocellular (59,60), glioma (61), breast (62,63), renal (64), and ovarian (65). KLF8 has been shown to regulate oncogenesis by promoting cellular proliferation and tumor invasion and by inhibiting apoptosis (21,(65)(66)(67)(68) Crossing these mice with Klf3 null mice results in embryonic lethality, indicative of a genetic interaction between these two factors.…”