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β-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: implications for a double-targeted therapy
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β-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: implications for a double-targeted therapy
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Journal Article
β-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: implications for a double-targeted therapy
2018
Overview
Nuclear activated
β
-catenin plays a causative role in colorectal cancers (CRC) but remains an elusive therapeutic target. Using human CRC cells harboring different Wnt/
β
-catenin pathway mutations in
APC/KRAS
or
β-catenin/KRAS
genes, and both genetic and pharmacological knockdown approaches, we show that oncogenic
β
-catenin signaling negatively regulates the expression of NHERF1 (Na
+
/H
+
exchanger 3 regulating factor 1), a PDZ-adaptor protein that is usually lost or downregulated in early dysplastic adenomas to exacerbate nuclear
β
-catenin activity. Chromatin immunoprecipitation (ChIP) assays demonstrated that
β
-catenin represses NHERF1 via TCF4 directly, while the association between TCF1 and the
Nherf1
promoter increased upon
β
-catenin knockdown. To note, the occurrence of a cytostatic survival response in settings of single
β
-catenin-depleted CRC cells was abrogated by combining NHERF1 inhibition via small hairpin RNA (shRNA) or RS5517, a novel PDZ1-domain ligand of NHERF1 that prevented its ectopic nuclear entry. Mechanistically, dual NHERF1/
β
-catenin targeting promoted an autophagy-to-apoptosis switch consistent with the activation of Caspase-3, the cleavage of PARP and reduced levels of phospho-ERK1/2, Beclin-1, and Rab7 autophagic proteins compared with
β
-catenin knockdown alone. Collectively, our data unveil novel
β
-catenin/TCF-dependent mechanisms of CRC carcinogenesis, also offering preclinical proof of concept for combining
β
-catenin and NHERF1 pharmacological inhibitors as a mechanism-based strategy to augment apoptotic death of CRC cells refractory to current Wnt/
β
-catenin-targeted therapeutics.
