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The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor.

ABSTRACT: Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase ?TRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

SUBMITTER: Karlin KL

PROVIDER: S-EPMC4427000 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor.

Karlin Kristen L KL Mondal Gourish G Hartman Jessica K JK Tyagi Siddhartha S Kurley Sarah J SJ Bland Chris S CS Hsu Tiffany Y T TY Renwick Alexander A Fang Justin E JE Migliaccio Ilenia I Callaway Celetta C Nair Amritha A Dominguez-Vidana Rocio R Nguyen Don X DX Osborne C Kent CK Schiff Rachel R Yu-Lee Li-Yuan LY Jung Sung Y SY Edwards Dean P DP Hilsenbeck Susan G SG Rosen Jeffrey M JM Zhang Xiang H-F XH Shaw Chad A CA Couch Fergus J FJ Westbrook Thomas F TF

Cell reports 20141106 4

Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a fr ...[more]

PMID: 25453754

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Project description:Background & Aims:Uncontrolled liver proliferation is a key characteristic of liver cancer; however, the mechanisms by which this occurs are not well understood. Elucidation of these mechanisms is necessary for the development of better therapy. The oncogene Gankyrin (Gank) is overexpressed in both hepatocellular carcinoma and hepatoblastoma. The aim of this work was to determine the role of Gank in liver proliferation and elucidate the mechanism by which Gank promotes liver proliferation. Methods:We generated Gank liver-specific knock-out (GLKO) mice and examined liver biology and proliferation after surgical resection and liver injury. Results:Global profiling of gene expression in GLKO mice showed significant changes in pathways involved in liver cancer and proliferation. Investigations of liver proliferation after partial hepatectomy and CCl4 treatment showed that GLKO mice have dramatically inhibited proliferation of hepatocytes at early stages after surgery and injury. In control LoxP mice, liver proliferation was characterized by Gank-mediated reduction of tumor-suppressor proteins (TSPs). The failure of GLKO hepatocytes to proliferate is associated with a lack of down-regulation of these proteins. Surprisingly, we found that hepatic progenitor cells of GLKO mice start proliferation at later stages and restore the original size of the liver at 14 days after partial hepatectomy. To examine the proliferative activities of Gank in cancer cells, we used a small molecule, cjoc42, to inhibit interactions of Gank with the 26S proteasome. These studies showed that Gank triggers degradation of TSPs and that cjoc42-mediated inhibition of Gank increases levels of TSPs and inhibits proliferation of cancer cells. Conclusions:These studies show that Gank promotes hepatocyte proliferation by elimination of TSPs. This work provides background for the development of Gank-mediated therapy for the treatment of liver cancer. RNA sequencing data can be accessed in the NCBI Gene Expression Omnibus: GSE104395.

Dataset Information

The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor.

Publications

The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor.

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