Regulating BRCA1 protein stability by cathepsin S-mediated ubiquitin degradation

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 doublestrand 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.

Exenatide inhibits NF-κB and attenuates ER stress in diabetic cardiomyocyte models

“…As discussed above, hyperglycemia-induced cardiomyocyte damage is associated with ER stress and NF-κB signaling pathway activation [23,24]. Accordingly, we observed alterations in ER stress and NF-κB activation in response to Exenatide treatment.…”

‘Patchiness’ and basic cancer research: unravelling the proteases

“…Meanwhile, Burton et al (2017) linked nuclear Cathepsin L with CUX1 proteolytic processing and thus linked Cathepsin L with EMT (and MET) progression in BC and PC cells [142]. Interestingly, in this study subcellular Cathepsin L was also observed to translocate from the nucleus to the cytoplasm, highlighting a novel protein trafficking-function for Cathepsin L. Kim et al (2018) showed that Cathepsin S could bind BRCA1 and facilitate it's ubiquitination and breakdown, thus suppressing DNA repair in BC development, while knocked-down expression of Cathepsin S stabilized BRCA1 levels, thus collectively linking Cathepsin S to BRCA1 signaling transduction [143]. As a novel substrate, Bian et al (2015) found Cathepsin B to colocalise and target p27 kip for degradation in CRC cells, thus linking it to cell cycle modulation [144].…”

BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

“…In addition, BRCA2 is becoming ubiquitinated and degraded during tumorigenesis which contributes to genomic instability and development of non-familial cancers 13, 139. A number of proteins have been identified as regulators of BRCA1/BRCA2 stability including cysteine protease Cathepsin S (CTSS) which interacts with the BRCT domain of BRCA1 and activates its proteolytic degradation 140, E2 ubiquitin-conjugating enzyme E2T (UBE2T) 139, E3 ubiquitin ligases Herc2 and F-box-protein 44 (FBXO44) which ubiquitinate and downregulate BRCA1 protein 141, 142. Interaction with BARD1 protein results in the reduction of proteasome-sensitive ubiquitination and stabilization of BRCA1 expression 143.…”