Abstract
Colorectal cancer (CRC) patients develop recurrence after chemotherapy owing to the survival of stem cell-like cells referred to as cancer stem-like cells (CSCs). The origin of CSCs is linked to the epithelial–mesenchymal transition (EMT) process. Currently, it remains poorly understood how EMT programmes enable CSCs residing in the tumour microenvironment to escape the effects of chemotherapy. This study identifies a key molecular pathway that is responsible for the formation of drug-resistant CSC populations. Using a modified yeast-2-hybrid system and 2D gel-based proteomics methods, we show that the E3-ubiquitin ligase FBXW7 directly binds and degrades the EMT-inducing transcription factor ZEB2 in a phosphorylation-dependent manner. Loss of FBXW7 induces an EMT that can be effectively reversed by knockdown of ZEB2. The FBXW7-ZEB2 axis regulates such important cancer cell features, as stemness/dedifferentiation, chemoresistance and cell migration in vitro, ex vivo and in animal models of metastasis. High expression of ZEB2 in cancer tissues defines the reduced ZEB2 expression in the cancer-associated stroma in patients and in murine intestinal organoids, demonstrating a tumour-stromal crosstalk that modulates a niche and EMT activation. Our study thus uncovers a new molecular mechanism, by which the CRC cells display differences in resistance to chemotherapy and metastatic potential.
Highlights
About 40–50% of patients with stage II and stage III colorectal cancer (CRC) exhibit resistance to therapy and develop recurrent cancer over the course of treatment[1]
We identified Fbxw7-associated proteins (FAPs) that were expressed in crypt/intestinal/colon stem cells (ISCs)-isolation followed by 2D-MALDIMS, which were phosphorylation-dependent targets of FBXW7 using the yeast-based, cytoplasmic two-hybrid Ras-Recruitment-System (RRS) assays[9]
We addressed how the FBXW7ZEB2 axis mediates an interplay between epithelial–mesenchymal transition (EMT), cancerassociated fibroblasts (CAFs) and CR-cancer stem-like cells (CSCs) and regulates CRC metastasis and chemoresistance
Summary
About 40–50% of patients with stage II and stage III colorectal cancer (CRC) exhibit resistance to therapy and develop recurrent cancer over the course of treatment[1]. CRC cells respond to transcriptional and epigenetic changes and undergo epithelial–mesenchymal transition (EMT). The EMT is associated with the cell capacity to selfrenew (termed cancer stem-like cells (CSCs)), generating. The specificity of proteolysis is determined by the association of a specific E3-receptor subunit with the substrate. FBXW7 ( called hCDC4, Fbw7) functions as a receptor subunit for the Skp1/Cullin/F-box (SCF)-E3 (SCFFBXW7) and targets several proteins with critical roles in the hallmarks of cancer[3,4]. Elucidating the FBXW7 mechanism(s) of action can add valuable information for identifying therapeutic targets and strategies to block CRC growth and metastasis.
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