TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma

Giacomo Lettini, Lorenza Sisinni, Valentina Condelli, Danilo Swann Matassa, Vittorio Simeon, Francesca Maddalena, Marica Gemei, Elvira Lopes, Giulia Vita, Luigi Del Vecchio, Franca Esposito, Matteo Landriscina

Research output: Contribution to journalArticlepeer-review

Abstract

Colorectal carcinoma (CRC) is a common cause of cancer-related death worldwide. Indeed, treatment failures are triggered by cancer stem cells (CSCs) that give rise to tumor repopulation upon initial remission. Thus, the role of the heat shock protein TRAP1 in stemness was investigated in CRC cell lines and human specimens, based on its involvement in colorectal carcinogenesis, through regulation of apoptosis, protein homeostasis and bioenergetics. Strikingly, co-expression between TRAP1 and stem cell markers was observed in stem cells located at the bottom of intestinal crypts and in CSCs sorted from CRC cell lines. Noteworthy, TRAP1 knockdown reduced the expression of stem cell markers and impaired colony formation, being the CSC phenotype and the anchorage-independent growth conserved in TRAP1-rich cancer cells. Consistently, the gene expression profiling of HCT116 cells showed that TRAP1 silencing results in the loss of the stem-like signature with acquisition of a more-differentiated phenotype and the downregulation of genes encoding for activating ligands and target proteins of Wnt/β-catenin pathway. Mechanistically, TRAP1 maintenance of stemness is mediated by the regulation of Wnt/β-catenin signaling, through the modulation of the expression of frizzled receptor ligands and the control of β-catenin ubiquitination/phosphorylation. Remarkably, TRAP1 is associated with higher expression of β-catenin and several Wnt/β-catenin target genes in human CRCs, thus supporting the relevance of TRAP1 regulation of β-catenin in human pathology. This study is the first demonstration that TRAP1 regulates stemness and Wnt/β-catenin pathway in CRC and provides novel landmarks in cancer biology and therapeutics.

Original languageEnglish
Pages (from-to)1792-1803
Number of pages12
JournalCell Death and Differentiation
Volume23
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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