DNAJB6 induces degradation of beta-catenin and causes partial reversal of mesenchymal phenotype.
We showed that expression of MRJ (DNAJB6) protein is lost in invasive ductal carcinoma, and restoration of MRJ(L) restricts malignant behavior of breast cancer and melanoma cells. However, the signaling pathways influenced by MRJ(L) are largely unknown. Our observations revealed that MRJ(L) expression causes changes in cell morphology concomitant with down-regulation of several mesenchymal markers, viz. vimentin, N-cadherin, Twist, and Slug, and up-regulation of epithelial marker keratin 18. Importantly, MRJ(L) expression led to reduced levels of beta-catenin, an epithelial mesenchymal transition marker, and a critical player in the Wnt pathway. We found that MRJ(L) up-regulates expression of DKK1, a well known Wnt/beta-catenin signaling inhibitor, that causes degradation of beta-catenin. Re-expression of DNAJB6 alters the Wnt/beta-catenin signaling in cancer cells, leading to partial reversal of the mesenchymal phenotype. Thus, MRJ(L) may play a role in maintaining an epithelial phenotype, and inhibition of the Wnt/beta-catenin pathway may be one of the potential mechanisms contributing to the restriction of malignant behavior by MRJ(L).
Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
Aparna
A
Mitra
Mitchell E
ME
Menezes
Lalita A
LA
Shevde
Rajeev S
RS
Samant
D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D014945:Wound Healing; D051176:beta Catenin / Q000378:metabolism*
C501126:DKK1 protein, human; C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex