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 β-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 β-catenin signaling. We confirmed this by showing β-catenin knockdown reduced ZNF277 expression and, using chromatin IP, identified 2 β-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 β-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.
Highlights
Despite advances in screening and treatment, in the U.S, colorectal cancer (CRC) is responsible for ~50,000 deaths yearly and remains the second leading cause of cancer death [1]
Β-catenin was prominently expressed in the cytoplasm and membranes of all enteroid cells (Supplemental Figure 1). These results indicate Zfp277 is selectively expressed in murine intestinal transitamplifying cells (TACs) but not in differentiated enterocytes
Intestinal epithelial homeostasis is maintained by intestinal stem and early progenitor TACs [35, 36]
Summary
Despite advances in screening and treatment, in the U.S, colorectal cancer (CRC) is responsible for ~50,000 deaths yearly and remains the second leading cause of cancer death [1]. Chemotherapy, and radiation for advanced metastatic disease have limited efficacy. In addition to limited efficacy, use of these agents is limited by off-target toxicity that reduces their tolerance; for example, treatment targeted at EGFR, which is expressed widely in non-intestinal epithelial cells, e.g., dermal epithelial cells [12], may cause severe skin reactions. These therapeutic limitations highlight the urgent need to identify novel molecular targets and approaches
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