Abstract
The tumor suppressor FBW7 targets oncoproteins such as c-MYC for ubiquitylation and is mutated in several human cancers. We noted that in a substantial percentage of colon cancers, FBW7 protein is undetectable despite the presence of FBW7 mRNA. To understand the molecular mechanism of FBW7 regulation in these cancers, we employed proteomics and identified the deubiquitinase (DUB) USP9X as an FBW7 interactor. USP9X antagonized FBW7 ubiquitylation, and Usp9x deletion caused Fbw7 destabilization. Mice lacking Usp9x in the gut showed reduced secretory cell differentiation and increased progenitor proliferation, phenocopying Fbw7 loss. In addition, Usp9x inactivation impaired intestinal regeneration and increased tumor burden in colitis-associated intestinal cancer. c-Myc heterozygosity abrogated increased progenitor proliferation and tumor burden in Usp9x-deficient mice, suggesting that Usp9x suppresses tumor formation by regulating Fbw7 protein stability and thereby reducing c-Myc. Thus, we identify a tumor suppressor mechanism in the mammalian intestine that arises from the posttranslational regulation of FBW7 by USP9X independent of somatic FBW7 mutations.
Highlights
The mammalian intestine is composed of repetitive differentiated and stem cell units called villi and crypts, respectively
To investigate the prevalence of altered posttranscriptional regulation of FBW7 protein in human colorectal cancers (CRCs), we performed in situ hybridization (RNAscope) and IHC for FBW7 on serial sections from tissue microarrays (TMAs) of patients with CRC
Multiple different shRNAs targeting USP9X caused a sharp decrease in endogenous FBW7, whereas RBX1 and SKP1 protein and FBW7 mRNA levels were unaffected (Figure 2, A and B). These results suggest that USP9X may control FBW7 protein stability and that FBW7 could be a USP9X substrate
Summary
The mammalian intestine is composed of repetitive differentiated and stem cell units called villi and crypts, respectively. Stem cells are located at the bottom of crypts, where they produce highly proliferating transit-amplifying (TA) cells. TA cells differentiate into absorptive and secretory cells, the two main intestinal lineages. The absorptive lineage comprises enterocytes, while the secretory lineage is composed of goblet (mucin-secreting), enteroendocrine (hormone-secreting), and Paneth cells (which produce lysozyme) [1]. Pathways including Wnt and Notch signaling [2] regulate the proliferation and differentiation of the mammalian gut epithelium. Wnt ligands activate β-catenin and increase expression of Wnt/T cell factor (TCF) target genes [3], including c-Myc, which is required for stem cell maintenance [2]. Notch signaling is active both in stem cells and in TA cells, where it controls cell fate decisions [4]
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