Cathepsin V regulates cell cycle progression and histone stability in the nucleus of breast cancer cells

Abstract

Introduction: We previously identified that Cathepsin V (CTSV) expression is associated with poor prognosis in ER+ breast cancer, particularly within the Luminal A subtype. Examination of the molecular role of the protease within Luminal A tumours, revealed that CTSV promotes tumour cell invasion and proliferation, in addition to degradation of the luminal transcription factor, GATA3, via the proteasome.Methods: Cell line models expressing CTSV shRNA or transfected to overexpress CTSV were used to examine the impact of CTSV on cell proliferation by MTT assay and flow cytometry. Western blotting analysis was used to identify the impact of CTSV on histone and chaperone protein expression. Cell fractionation and confocal microscopy was used to illustrate the presence of CTSV in the nuclear compartment.Results: In this work we have identified that CTSV has an impact on breast cancer cell proliferation, with CTSV depleted cells exhibiting delayed progression through the G2/M phase of the cell cycle. Further investigation has revealed that CTSV can control nuclear expression levels of histones H3 and H4 via regulating protein expression of their chaperone sNASP. We have discovered that CTSV is localised to the nuclear compartment in breast tumour cells, mediated by a bipartite nuclear localisation signal (NLS) within the CTSV sequence and that nuclear CTSV is required for cell cycle progression and histone stability in breast tumour cells.Discussion: Collectively these findings support the hypothesis that targeting CTSV may have utility as a novel therapeutic target in ER+ breast cancer by impairing cell cycle progression via manipulating histone stabilisation.

The causal relationship between cathepsins and digestive system tumors: a Mendelian randomization study

“…Furthermore, it has been found that cathepsin L2 can also drive the progression of lung cancer by influencing the immunosuppressive environment and the cleavage of adhesion molecules ( 47 ). Furthermore, the activity of cathepsin L2 has been demonstrated to govern the advancement of the cell cycle and maintain the stability of histones within the nucleus of malignant cells found in breast cancer ( 49 ). It is also closely associated with the prognosis of HCC and the tumor microenvironment ( 50 ).…”