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

Gemma Ferrer-Mayorga, Silvia Alvarez-Díaz, Noelia Valle, Javier De Las Rivas, Marta Mendes, Rodrigo Barderas, Francesc Canals, Olga Tapia, J. Ignacio Casal, Miguel Lafarga, Alberto Muñoz*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)

Abstract

Cystatin D is an inhibitor of lysosomal and secreted cysteine proteases. Strikingly, cystatin D has been found to inhibit proliferation, migration, and invasionofcolon 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 nucleusatspecific transcriptionally active chromatin sites. Consistently, transcriptomic analysis show that cystatin Dalters 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 arrayswefound that cystatin Dreduces 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.

Original languageEnglish
Pages (from-to)26533-26548
Number of pages16
JournalJournal of Biological Chemistry
Volume290
Issue number44
DOIs
Publication statusPublished - 30 Oct 2015
Externally publishedYes

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