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Title

Cystatin D locates in the nucleus at sites of active transcription and modulates gene and protein expression

AuthorsFerrer-Mayorga, Gemma ; Álvarez-Díaz, S.; Valle, Noelia ; De Las Rivas, Javier ; Mendes, Marta; Barderas, Rodrigo ; Casal, J. Ignacio ; Lafarga, Miguel; Muñoz Terol, Alberto
KeywordsColon cancer
Cysteine protease
Cytokine
Gene expression
Protease inhibitor
Issue Date30-Oct-2015
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 290(44): 26533-26548 (2015)
AbstractCystatin D is an inhibitor of lysosomal and secreted cysteine proteases. Strikingly, cystatin D has been found to inhibit proliferation, migration, and invasion of colon carcinoma cells indicating tumor suppressor activity that is unrelated to protease inhibition. Here, we demonstrate that a proportion of cystatin D locates within the cell nucleus at specific transcriptionally active chromatin sites. Consistently, transcriptomic analysis show that cystatin D alters gene expression, including that of genes encoding transcription factors such as RUNX1, RUNX2, and MEF2C in HCT116 cells. In concordance with transcriptomic data, quantitative proteomic analysis identified 292 proteins differentially expressed in cystatin D-expressing cells involved in cell adhesion, cytoskeleton, and RNA synthesis and processing. Furthermore, using cytokine arrays we found that cystatin D reduces the secretion of several protumor cytokines such as fibroblast growth factor-4, CX3CL1/fractalkine, neurotrophin 4 oncostatin-M, pulmonary and activation-regulated chemokine/CCL18, and transforming growth factor B3. These results support an unanticipated role of cystatin D in the cell nucleus, controlling the transcription of specific genes involved in crucial cellular functions, which may mediate its protective action in colon cancer.
DescriptionFerrer-Mayorga, Gemma et al.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M115.660175
URIhttp://hdl.handle.net/10261/129490
DOI10.1074/jbc.M115.660175
ISSN0021-9258
E-ISSN1083-351X
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(IIBM) Artículos
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