TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation
Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulatin...
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doaj-19034249c8914e1f8ced42be4cbc536e2020-11-25T03:54:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-01217526752610.3390/ijms21207526TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression ModulationGiacomo Lettini0Valentina Condelli1Michele Pietrafesa2Fabiana Crispo3Pietro Zoppoli4Francesca Maddalena5Ilaria Laurenzana6Alessandro Sgambato7Franca Esposito8Matteo Landriscina9Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyDepartment of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, PZ, ItalyWnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.https://www.mdpi.com/1422-0067/21/20/7526molecular chaperoneTRAP1Wnt signalingcancer stem cellcolon cancerstemness |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Giacomo Lettini Valentina Condelli Michele Pietrafesa Fabiana Crispo Pietro Zoppoli Francesca Maddalena Ilaria Laurenzana Alessandro Sgambato Franca Esposito Matteo Landriscina |
spellingShingle |
Giacomo Lettini Valentina Condelli Michele Pietrafesa Fabiana Crispo Pietro Zoppoli Francesca Maddalena Ilaria Laurenzana Alessandro Sgambato Franca Esposito Matteo Landriscina TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation International Journal of Molecular Sciences molecular chaperone TRAP1 Wnt signaling cancer stem cell colon cancer stemness |
author_facet |
Giacomo Lettini Valentina Condelli Michele Pietrafesa Fabiana Crispo Pietro Zoppoli Francesca Maddalena Ilaria Laurenzana Alessandro Sgambato Franca Esposito Matteo Landriscina |
author_sort |
Giacomo Lettini |
title |
TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation |
title_short |
TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation |
title_full |
TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation |
title_fullStr |
TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation |
title_full_unstemmed |
TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation |
title_sort |
trap1 regulates wnt/β-catenin pathway through lrp5/6 receptors expression modulation |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-10-01 |
description |
Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1. |
topic |
molecular chaperone TRAP1 Wnt signaling cancer stem cell colon cancer stemness |
url |
https://www.mdpi.com/1422-0067/21/20/7526 |
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