Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1

Jae Hun Shin; Jaekwang Jeong; Jungmin Choi; Jaechul Lim; Ravi K Dinesh; Jonathan Braverman; Jun Young Hong; Stephen E Maher; Maria C Amezcua Vesely; WonJu Kim; Ja-Hyun Koo; Wenwen Tang; Dianqing Wu; Holly N Blackburn; Rosa M Xicola; Xavier Llor; Omer Yilmaz; Je-Min Choi; Alfred L M Bothwell

doi:10.1016/j.isci.2021.102411

Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1

iScience. 2021 Apr 15;24(5):102411. doi: 10.1016/j.isci.2021.102411. eCollection 2021 May 21.

Authors

Jae Hun Shin¹, Jaekwang Jeong², Jungmin Choi^{3

4}, Jaechul Lim¹, Ravi K Dinesh¹, Jonathan Braverman⁵, Jun Young Hong¹, Stephen E Maher¹, Maria C Amezcua Vesely¹, WonJu Kim⁶, Ja-Hyun Koo⁶, Wenwen Tang⁷, Dianqing Wu⁷, Holly N Blackburn^{1

8}, Rosa M Xicola⁹, Xavier Llor⁹, Omer Yilmaz^{5

10}, Je-Min Choi⁶, Alfred L M Bothwell¹

Affiliations

¹ Department of Immunobiology, Yale University School of Medicine, TAC 641D, PO Box 208011, 300 Cedar Street, New Haven, CT 06520-8011, USA.
² Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
³ Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
⁴ Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.
⁵ The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Department of Life Science, College of Natural Science, Hanyang University, Seoul 04763, Republic of Korea.
⁷ Vascular Biology and Therapeutic Program and Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
⁸ Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA.
⁹ Department of Medicine and Cancer Center, Yale University, New Haven, CT 06520, USA.
¹⁰ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Abstract

Enhanced stemness in colorectal cancer has been reported and it contributes to aggressive progression, but the underlying mechanisms remain unclear. Here we report a Wnt ligand, Dickkopf-2 (DKK2) is essential for developing colorectal cancer stemness. Genetic depletion of DKK2 in intestinal epithelial or stem cells reduced tumorigenesis and expression of the stem cell marker genes including LGR5 in a model of colitis-associated cancer. Sequential mutations in APC, KRAS, TP53, and SMAD4 genes in colonic organoids revealed a significant increase of DKK2 expression by APC knockout and further increased by additional KRAS and TP53 mutations. Moreover, DKK2 activates proto-oncogene tyrosine-protein kinse Src followed by increased LGR5 expressing cells in colorectal cancer through degradation of HNF4α1 protein. These findings suggest that DKK2 is required for colonic epithelial cells to enhance LGR5 expression during the progression of colorectal cancer.

Keywords: Cancer; Cell Biology; Stem Cells Research.

Abstract

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