TCF7L1 recruits CtBP and HDAC1 to repress DICKKOPF4 gene expression in human colorectal cancer cells.

The T-cell factor/Lymphoid enhancer factor (TCF/LEF; hereafter TCF) family of transcription factors are critical regulators of colorectal cancer (CRC) cell growth. Of the four TCF family members, TCF7L1 functions predominantly as a repressor of gene expression. Few studies have addressed the role of TCF7L1 in CRC and only a handful of target genes regulated by this repressor are known. By silencing TCF7L1 expression in HCT116 cells, we show that it promotes cell proliferation and tumorigenesis in vivo by driving cell cycle progression. Microarray analysis of transcripts differentially expressed in control and TCF7L1-silenced CRC cells identified genes that control cell cycle kinetics and cancer pathways. Among these, expression of the Wnt antagonist DICKKOPF4 (DKK4) was upregulated when TCF7L1 levels were reduced. We found that TCF7L1 recruits the C-terminal binding protein (CtBP) and histone deacetylase 1 (HDAC1) to the DKK4 promoter to repress DKK4 gene expression. In the absence of TCF7L1, TCF7L2 and ß-catenin occupancy at the DKK4 promoter is stimulated and DKK4 expression is increased. These findings uncover a critical role for TCF7L1 in repressing DKK4 gene expression to promote the oncogenic potential of CRCs.

Dickkopf-4 is frequently overexpressed in epithelial ovarian carcinoma and promotes tumor invasion.

BACKGROUND: Dickkopf-4 (DKK4), a member of DKK family, appears to be a divergent protein. It remained multi-biological functions in carcinogenesis. The effect of DKK4 on the ovarian cancer cells remains unclear. This study detected the clinical significance of DKK4 in epithelial ovarian cancer (EOC) patients and its role in invasion. METHODS: QRT-PCR and western blot analysis were used to examine the levels of DKK4 mRNA and protein in 33 EOC tissues and 33 benign ovarian tumors. Immunohistochemical analysis was performed to assess DKK4 expression in 239 EOC samples. siRNA-mediated DKK4 silence was conducted. Transwell assay was used to detect the invasive ability. Phalloidin was used to stain the formations of actin filaments. RESULTS: The expressions of DKK4 mRNA and protein were elevated in EOC tissues as compared with those in benign ovarian tumors (p = 0.001 and <0.0001 respectively). Immunohistochemical results showed the strong expression of DKK4 protein was positively associated with late FIGO stage (p = 0.005) and poor disease free survival in univariate and multivariate analysis (p < 0.0001 and p = 0.001, respectively). SiRNA-mediated DKK4 knockdown inhibited cell invasive ability (all p < 0.0001) and the formations of actin filaments. DKK4 could promote the phosphration of c-JUN and JNK (p < 0.0001 and p = 0.001, respectively). CONCLUSIONS: Our results indicated that DKK4 might be contributed to predicting EOC progression and prognosis. DKK4 could promote the invasion of EOC through JNK activation.

Dickkopf-4 gene expression is associated with differentiation and lymph node metastasis in colorectal cancer.

BACKGROUND AND AIM: Although high expression of Dickkopf-4 (DKK-4) in colorectal cancer has been reported in previous studies, its impact on clinicopathological features, including the prognosis and mechanism of expression, has not been well clarified to date. METHODS: (i) DKK-4 protein expression was analyzed by immunohistochemical staining with anti-DKK-4 antibody using archived formalin-fixed paraffin-embedded specimens obtained at surgery from 122 patients with colorectal cancer, and its association with clinicopathological findings was also investigated. (ii) The association between intratumoral DKK-4 protein expression and somatic hotspot mutations in cancer-associated genes in 40 patients was investigated using a next-generation sequencer. RESULTS: In cross-section, DKK-4 protein expression in colorectal tissue was related to an adenocarcinoma of a histologically differentiated type (tub1/tub2, P = 0.032) and distant metastasis (P = 0.012). Longitudinally, however, DKK-4 was not an independent prognostic factor determining overall survival (OS). On the other hand, in patients with metastasis, high DKK-4 protein was independently associated with short OS (P = 0.013). In addition, colorectal cancer tissue with high DKK-4 protein expression was associated with hotspot mutations in Wnt/ß catenin-signaling molecules (APC, CTNNB1, and FBXW7, P = 0.03). CONCLUSION: Intratumoral DKK-4 expression, by partly reflecting the Wnt/ß catenin pathway, is strongly associated with the advancement of colorectal cancer and OS in colorectal cancer patients with metastasis, although further studies are needed.