The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer

Cells. 2023 Dec 29;13(1):75. doi: 10.3390/cells13010075.

Abstract

The human Dickkopf (DKK) family includes four main secreted proteins, DKK-1, DKK-2, DKK-3, and DKK-4, as well as the DKK-3 related protein soggy (Sgy-1 or DKKL1). These glycoproteins play crucial roles in various biological processes, and especially modulation of the Wnt signaling pathway. DKK-3 is distinct, with its multifaceted roles in development, stem cell differentiation and tissue homeostasis. Intriguingly, DKK-3 appears to have immunomodulatory functions and a complex role in cancer, acting as either a tumor suppressor or an oncogene, depending on the context. DKK-3 is a promising diagnostic and therapeutic target that can be modulated by epigenetic reactivation, gene therapy and DKK-3-blocking agents. However, further research is needed to optimize DKK-3-based therapies. In this review, we comprehensively describe the known functions of DKK-3 and highlight the importance of context in understanding and exploiting its roles in health and disease.

Keywords: DKK-3; Dickkopf (DKK) family; Wnt signaling pathway; cancer; development; immunomodulation; oncogene; therapy; tumor suppressor.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Epigenomics
  • Genetic Therapy
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Neoplasms* / genetics
  • Oncogenes*

Substances

  • DKKL1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • DKK3 protein, human

Grants and funding

J.M. is financially supported by a PhD fellowship awarded by the French national “Ligue Contre le Cancer”. C.T. is financially supported by a PhD fellowship awarded by the Ministère de l’Enseignement Supérieur et de la Recherche. B.W. is an Emeritus Research Director in the CNRS hosted by Irwin Davidson’s team, Department of Functional Genomics and Cancer, IGBMC (2016–2026). The Laboratoire de Biologie Tumorale and the STREINTH team are supported by the Conférence de Coordination Interrégionale Grand Est-Bourgogne Franche-Comté de la Ligue Contre le Cancer, the Institut de cancérologie Strasbourg Europe, the Association pour la Recherche sur le Cancer, ITMO Cancer, European action COST Proteocure, the Interdisciplinary thematic Institute InnoVec, the IDEX Excellence grant from Unistra, and the Institut National du Cancer.