Deptor is a novel target of Wnt/β-Catenin/c-Myc and contributes to colorectal cancer cell growth

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50 Scopus citations


Activation of the Wnt/β-catenin signaling pathway drives colorectal cancer growth by deregulating expression of downstream target genes, including the c-myc proto-oncogene. The critical targets that mediate the functions of oncogenic c-Myc in colorectal cancer have yet to be fully elucidated. Previously, we showed that activation of PI3K/Akt/mTOR contributes to colorectal cancer growth and metastasis. Here, we show that Deptor, a suppressor of mTOR, is a direct target of Wnt/β-catenin/c-Myc signaling in colorectal cancer cells. Inhibition of Wnt/β-catenin or knockdown of c-Myc decreased, while activation of Wnt/β-catenin or overexpression of c-Myc increased the expression of Deptor. c-Myc bound the promoter of Deptor and transcriptionally regulated Deptor expression. Inhibition of Wnt/β-catenin/c-Myc signaling increased mTOR activation, and the combination of Wnt and Akt/mTOR inhibitors enhanced inhibition of colorectal cancer cell growth in vitro and in vivo. Deptor expression was increased in colorectal cancer cells; knockdown of Deptor induced differentiation, decreased expression of B lymphoma Mo-MLV insertion region 1 (Bmi1), and decreased proliferation in colorectal cancer cell lines and primary human colorectal cancer cells. Importantly, our work identifies Deptor as a downstream target of the Wnt/β-catenin/c-Myc signaling pathway, acting as a tumor promoter in colorectal cancer cells. Moreover, we provide a molecular basis for the synergistic combination of Wnt andmTORinhibitors in treating colorectal cancer with elevated c-Myc. Significance: The mTOR inhibitor DEPTOR acts as a tumor promoter and could be a potential therapeutic target in colorectal cancer.

Original languageEnglish
Pages (from-to)3163-3175
Number of pages13
JournalCancer Research
Issue number12
StatePublished - Jun 15 2018

Bibliographical note

Funding Information:
The authors thank Donna Gilbreath and Heather N. Russell-Simmons for manuscript preparation; D. Napier for tissue sectioning and staining; Tianxin Yu for tissue collection from ApcMin mice. We also acknowledge support from the University of Kentucky Markey Cancer Center's Biostatistics and Bioinformatics Shared Resource Facility and the Biospecimen Procurement and Translational Pathology Shared Resource Facility. This work was supported by NIH grants R01 DK48498, R01 CA172379, T32 CA160003, and P30 CA177558.

Publisher Copyright:
© 2018 AACR.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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