Dickkopf-related protein 4 (DKK4)

Dickkopf-related protein 4 (DKK4) is a secreted inhibitor of the canonical Wnt signaling pathway, belonging to the Dickkopf protein family. It acts mainly by binding to the Wnt co-receptors LRP5/6 and the co-factor Kremen 2, blocking the formation of the Frizzled-LRP6 complex and promoting internalization of LRP5/6, thereby repressing β-catenin stabilization and Wnt pathway activation[1][3]. DKK4 is essential for embryonic development, regulating processes such as axis patterning and limb formation, and continues to play roles in tissue homeostasis in adults. Aberrant DKK4 expression is implicated in tumorigenesis, particularly in colorectal cancer and hepatocellular carcinoma, where it has both suppressive and promoting effects on tumor progression depending on expression context and tumor subtype[1][2][3]. It is also associated with bone pathophysiology and Alzheimer's disease in adults[3]. Elevated DKK4 may be a biomarker for poor prognosis and chemotherapy resistance in cancer, and its regulation by triiodothyronine (T3) and vitamin D receptor links it to broader physiological and therapeutic pathways[2]. No approved direct DKK4-targeting drugs exist, but modulating its pathway interactions has potential for cancer treatment, albeit with challenges due to its pleiotropic biological functions and complex roles in disease progression.

Other names

Dickkopf Wnt signaling pathway inhibitor 4Dickkopf-4Dkk-4hDkk-4DKK-4

*5-fluorouracil* and *YN968D1*: DKK4 may increase resistance to these drugs in colorectal cancer cells[2] by promoting cell migration and apoptosis. *1α, 25-dihydroxyvitamin D3*: inhibits DKK4 expression directly via its receptor and via TCF/β-catenin connection sites, possibly reversing resistance mechanisms[2].