The Role Of UHRF2 Gene In Colorectal Cancer

The epithelium of mammalian intestine has a tight cellular hierarchy and a remarkably renewing rate which can refresh every 3 to 5 days.The stem cells located in the crypt continuous proliferate to generate the progenitor cells which will differentiate into mature cells when migrate out of crypt.Breaking the balance of this routinized prolifertion and differentiation state will influence the the epithelial barrier function or even lead to cancer.Growing evidence has suggested tumors like colorectal cancers still retain a similar cellular hierarchy compared with the normal intestinal epithelium.Moreover,many genetic mouse models studies have demonstrated that cancer can originate from the mutations occuring in the normal stem cells.To understand the mechanisms that govern the normal homeostatic stem cells and its counterpart in tumors will be meaningful for the stem cell research and cancer therapy.According to the report,we find UHRF2,one of the UHRF gene family,is highly expressed in intestinal Lgr5+ stem cells.Besides,UHRF2 is upregulated in many human cancers including the colorectal cancer.It is reported that the expression level of UHRF2 is negatively correlated with the survival of the colorectal cancer patients.These data suggest UHRF2 possibly paly important roles in maintaining intestinal stem cells and cancer.To explore the fuction in vivo,We first generate the Uhrf2 knockout mouse.We find that the intestinal homostasis wasn’t disturbed in normal condition after Uhrf2 kncokout and Uhrf2 wasn’t required in damage induced intestinal regeneration.For further study of Uhrf2 in intestinal cancer,we established the spontaneous intestinal tumor model by crossing with the ApcMin mice.Unexpectedly,Uhrf2 deficiency significantly inhibit the tumor formtion with reduced polyps number and size,and prolong mice survival.Further study revealed that loss of Uhrf2 greatly delayed tumor initiation and supressed the tumor stem cells pool.Mechanistically,UHRF2,induced by hyperactive Wnt signaling in tumor,can interact with and stablize TCF4 through its RING domain mediated SUMOylation which can repress ubiquitin-mediated TCF4 degradation.Together,our data demonstrate the crucial role of Uhrf2 in maintaining tumor stem cells needed to sustain Wnt-driven tumor initiation and progression in the intestine.Uhrf2 could be a valuable target to tumor stem cells in intestinal cancer therapy,given the fact that Uhrf2 deficiency did not interfere homeostasis in normal intestine.