Dataset Information

USP11 Enhances TGF?-Induced Epithelial-Mesenchymal Plasticity and Human Breast Cancer Metastasis.

ABSTRACT: Epithelial-mesenchymal transition (EMT) is a conserved cellular plasticity program that is reactivated in carcinoma cells and drives metastasis. Although EMT is well studied its regulatory mechanisms remain unclear. Therefore, to identify novel regulators of EMT, a data mining approach was taken using published microarray data and a group of deubiquitinases (DUB) were found to be upregulated in cells that have undergone EMT. Here, it is demonstrated that one DUB, ubiquitin-specific peptidase 11 (USP11), enhances TGF?-induced EMT and self-renewal in immortalized human mammary epithelial cells. Furthermore, modulating USP11 expression in human breast cancer cells altered the migratory capacity in vitro and metastasis in vivo Moreover, elevated USP11 expression in human breast cancer patient clinical specimens correlated with decreased survival. Mechanistically, modulating USP11 expression altered the stability of TGF? receptor type II (TGFBR2) and TGF? downstream signaling in human breast cancer cells. Together, these data suggest that deubiquitination of TGFBR2 by USP11 effectively spares TGFBR2 from proteasomal degradation to promote EMT and metastasis.Implications: USP11 regulates TGF?-induced epithelial-mesenchymal plasticity and human breast cancer metastasis and may be a potential therapeutic target for breast cancer. Mol Cancer Res; 16(7); 1172-84. ©2018 AACR.

SUBMITTER: Garcia DA

PROVIDER: S-EPMC6030438 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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USP11 Enhances TGFβ-Induced Epithelial-Mesenchymal Plasticity and Human Breast Cancer Metastasis.

Garcia Daniel A DA Baek Christina C Estrada M Valeria MV Tysl Tiffani T Bennett Eric J EJ Yang Jing J Chang John T JT

Molecular cancer research : MCR 20180503 7

Epithelial-mesenchymal transition (EMT) is a conserved cellular plasticity program that is reactivated in carcinoma cells and drives metastasis. Although EMT is well studied its regulatory mechanisms remain unclear. Therefore, to identify novel regulators of EMT, a data mining approach was taken using published microarray data and a group of deubiquitinases (DUB) were found to be upregulated in cells that have undergone EMT. Here, it is demonstrated that one DUB, ubiquitin-specific peptidase 11 ...[more]

PMID: 29724812

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Project description:The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal-epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells. SIGNIFICANCE: These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1831/F1.large.jpg.See related commentary by Farrington and Narla, p. 1756.

Dataset Information

USP11 Enhances TGF?-Induced Epithelial-Mesenchymal Plasticity and Human Breast Cancer Metastasis.

Publications

USP11 Enhances TGFβ-Induced Epithelial-Mesenchymal Plasticity and Human Breast Cancer Metastasis.

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