Regulating BRCA1 protein stability by cathepsin S-mediated ubiquitin degradation

Seo Young Kim, Hee Jin, Hang Rhan Seo, Hae June Lee, Yun Sil Lee

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Cathepsin S (CTSS) is a cysteine protease that is thought to play a role in many physiological and pathological processes including tumor growth, angiogenesis, and metastasis; it has been identified as a radiation response gene. Here, we examined the role of CTSS in regulating the DNA damage response in breast cancer cells. Activating CTSS (producing the cleavage form of the protein) by radiation induced proteolytic degradation of BRCA1, which ultimately suppressed DNA double-strand break repair activity. Depletion of CTSS by RNAi or expression of a mutant type of CTSS enhanced the protein stability of BRCA1 by inhibiting its ubiquitination. CTSS interacted with the BRCT domain of BRCA1 and facilitated ubiquitin-mediated proteolytic degradation of BRCA1, which was tightly associated with decreased BRCA1-mediated DNA repair activity. Treatment with a pharmacological CTSS inhibitor inhibited proteolytic degradation of BRCA1 and restored BRCA1 function. Depletion of CTSS by shRNA delayed tumor growth in a xenograft mouse model, only in the presence of functional BRCA1. Spontaneously uced rat mammary tumors and human breast cancer tissues with high levels of CTSS expression showed low BRCA1 expression. From these data, we suggest that CTSS inhibition is a good strategy for functional restoration of BRCA1 in breast cancers with reduced BRCA1 protein stability.

Original languageEnglish
Pages (from-to)812-825
Number of pages14
JournalCell Death and Differentiation
Volume26
Issue number5
DOIs
StatePublished - 1 May 2019

Bibliographical note

Funding Information:
Acknowledgements This work was supported by grants from the National Research Foundation of Korea, (NRF-2015M2A2A7A03044831, NRF-2017R1A2B2002327, and NRF-2017M2A2A702019560), funded by the Korean government (Ministry of Science and ICT).

Publisher Copyright:
© 2018, ADMC Associazione Differenziamento e Morte Cellulare.

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