Reference SummaryXie G, JCI Insight 2022 Feb 22;7(4):e150894

Title

 Zinc finger protein 277 is an intestinal transit-amplifying cell marker and colon cancer oncogene.

Authors

 Xie G; Peng Z; Liang J; Larabee SM; Drachenberg CB; Yfantis H; Raufman JP

Journal

 JCI Insight

Volume

 7

Issue

 4

Year

 2022

Pages

 e150894

Abstract

 Sustained proliferative signaling and resisting cell death are hallmarks of cancer. Zinc finger protein 277 (ZNF277; murine Zfp277), a transcription factor regulating cellular senescence, is overexpressed in colon cancer, but its actions in intestinal homeostasis and neoplasia are unclear. Using human and murine intestine, human colon cancer cells, and ApcMin/+ mice with dysregulated beta-catenin signaling and exuberant intestinal neoplasia, we explored the actions of ZNF277/Zfp277 and defined the underlying mechanisms. In normal human and murine intestine, ZNF277/Zfp277 was expressed uniquely in early stem cell progenitors, undifferentiated transit-amplifying cells (TACs). Zfp277 was overexpressed in the ApcMin/+ mouse colon, implicating ZNF277/Zfp277 as a transcriptional target of beta-catenin signaling. We confirmed this by showing beta-catenin knockdown reduced ZNF277 expression and, using chromatin IP, identified 2 beta-catenin binding sites in the ZNF277 promoter. Zfp277 deficiency attenuated intestinal epithelial cell proliferation and tumor formation, and it strikingly prolonged ApcMin/+ mouse survival. RNA-Seq and PCR analyses revealed that Zfp277 modulates expression of genes in key cancer pathways, including beta-catenin signaling, the HOXD family that regulates development, and p21WAF1, a cell cycle inhibitor and tumor suppressor. In both human colon cancer cells and the murine colon, ZNF277/Zfp277 deficiency induced p21WAF1 expression and promoted senescence. Our findings identify ZNF277/Zfp277 as both a TAC marker and colon cancer oncogene that regulates cellular proliferation and senescence, in part by repressing p21WAF1 expression.

Links

 J:321515 – MGI References
35015732 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon adenoma Intestine - Large Intestine - Colon

observed
C57BL/6-ApcMin/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

83 - 100
C57BL/6-ApcMin/+ Zfp277tm1Aiwa/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

63 - 75
C57BL/6-C57BL/6-ApcMin/+ Zfp277tm1Aiwa Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

40 - 44
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Distal tumor Intestine - Small Intestine - Distal

observed
C57BL/6-C57BL/6-ApcMin/+ Zfp277tm1Aiwa Intestine - Small Intestine - Distal tumor Intestine - Small Intestine - Distal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Medial tumor Intestine - Small Intestine - Medial

observed
C57BL/6-C57BL/6-ApcMin/+ Zfp277tm1Aiwa Intestine - Small Intestine - Medial tumor Intestine - Small Intestine - Medial

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Proximal tumor Intestine - Small Intestine - Proximal

observed
C57BL/6-C57BL/6-ApcMin/+ Zfp277tm1Aiwa Intestine - Small Intestine - Proximal tumor Intestine - Small Intestine - Proximal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine adenoma Intestine - Small Intestine

observed
C57BL/6-C57BL/6-ApcMin/+ Zfp277tm1Aiwa Intestine - Small Intestine adenoma Intestine - Small Intestine

observed
C57BL/6-ApcMin/+ Intestine - Small Intestine tumor Intestine - Small Intestine

100
C57BL/6-ApcMin/+ Zfp277tm1Aiwa/+ Intestine - Small Intestine tumor Intestine - Small Intestine

100
C57BL/6-C57BL/6-ApcMin/+ Zfp277tm1Aiwa Intestine - Small Intestine tumor Intestine - Small Intestine

observed - 89
C57BL/6J-ApcMin/+ Intestine - Small Intestine tumor Intestine - Small Intestine

observed