Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

Abstract

The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P ¼ 0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P ¼ 0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of b-catenin. Knockdown of CXXC4 induced the nuclear translocation of b-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

“…49). Low levels of CXXC4 were observed in gastric and renal carcinomas and were associated with b-catenin nuclear translocation, metastasis formation, and poor prognosis (50). Furthermore, elevated EZH2 expression in breast CSCs (CD44 þ /CD24 low ) causes epigenetic silencing of the DNA repair factor RAD51, which in turn stimulates RAF1-ERK activity.…”

TET proteins in malignant hematopoiesis

“…IDAX (CXXC4) is described to function as a negative regulator of Wntsignaling, which represents an important signal transduction pathway regulating cell proliferation. 41,42 Disruption of this pathway has been described in a variety of malignant diseases. Like IDAX, RINF (CXXC5) was recently associated with the Wnt signaling pathway.…”

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia

“…15 Inactivation of CXXC4, the paralog of CXXC5, has been associated with tumor progression and inferior outcome in renal cell carcinoma. 16 CXXC5 is located on 5q31.2, a region recurrently deleted in AML, and was found to be downregulated in AML with del(5q). 17 In addition, somatic microdeletions containing CXXC5 (and CXXC4) have been described in patients with AML and myelodysplastic syndrome (MDS), 18,19 further supporting involvement of CXXC5 in leukemogenesis.…”