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Deptor Is a Novel Target of Wnt/?-Catenin/c-Myc and Contributes to Colorectal Cancer Cell Growth.

ABSTRACT: Activation of the Wnt/?-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/?-catenin/c-Myc signaling in colorectal cancer cells. Inhibition of Wnt/?-catenin or knockdown of c-Myc decreased, while activation of Wnt/?-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/?-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/?-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 and mTOR inhibitors 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. Cancer Res; 78(12); 3163-75. ©2018 AACR.

SUBMITTER: Wang Q

PROVIDER: S-EPMC6004255 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Deptor Is a Novel Target of Wnt/β-Catenin/c-Myc and Contributes to Colorectal Cancer Cell Growth.

Wang Qingding Q Zhou Yuning Y Rychahou Piotr P Harris Jennifer W JW Zaytseva Yekaterina Y YY Liu Jinpeng J Wang Chi C Weiss Heidi L HL Liu Chunming C Lee Eun Y EY Evers B Mark BM

Cancer research 20180417 12

Activation of the Wnt/β-catenin signaling pathway drives colorectal cancer growth by deregulating expression of downstream target genes, including the <i>c-myc</i> 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-M ...[more]

PMID: 29666061

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Dataset Information

Deptor Is a Novel Target of Wnt/?-Catenin/c-Myc and Contributes to Colorectal Cancer Cell Growth.

Publications

Deptor Is a Novel Target of Wnt/β-Catenin/c-Myc and Contributes to Colorectal Cancer Cell Growth.

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