Abstract
Autophagy is involved in modulating tumor cell motility and invasion, resistance to epithelial-to-mesenchymal transition, anoikis, and escape from immune surveillance. We have previous shown that SAHA is capable to induce several apoptosis and autophagy-related gene expression in breast cancers. However, the exact mechanisms of autophagy activation in this context have not been fully identified. Our results showed that the expression and the activity of Cathepsin B (CTSB), one of the major lysosomal cysteine proteases, were significantly increased in MDA-MB- 231 and MCF-7 cells upon SAHA treatment. We confirmed that Cystatin C, a protease inhibitor, significantly inhibited the expression of CTSB induced by SAHA on breast cancer cells. We demonstrated that SAHA is able to promote the expression of LC3II, a key member in the maturation of the autophagosome, the central organelle of autophagy in breast cancer cells. However, SAHA induced LC3II expression is effectively suppressed after the addition of Cystatin C to the cell culture. In addition, we identified a number of genes, as well as the mitogen-activated protein kinase (MAPK) signaling that is potentially involved in the action of SAHA and CTSB in the breast cancer cells. Overall, our results revealed that the autophagy-related genes are induced by SAHA via the activation of CTSB in breast cancer cells. An improved understanding of SAHA molecular mechanisms in breast cancer may facilitate SAHA clinical use and the selection of suitable combinations.
Highlights
Breast cancer remains as the most common malignant disease in women in the world [1]
Our results revealed that the autophagy-related genes are induced by SAHA via the activation of Cathepsin B (CTSB) in breast cancer cells
The results revealed that the expression of CTSB were significantly increased in MDA-MB- 231 and MCF-7 cells when Cystatin C was 0 ng/ml, which indicated that SAHA increased the expression of CTSB
Summary
Breast cancer remains as the most common malignant disease in women in the world [1]. Patients with ER-negative breast cancer often present high degrees of malignancy, aggression, and poor prognosis despite initial responsiveness to chemotherapy [2,3]. Epigenetic processes are direct heritable changes in gene expression without involving direct changes to the DNA sequences and play an important role in carcinogenesis [4,5,6]. Both the active and silent epigenetic www.impactjournals.com/oncotarget genes are controlled by the processes of addition or removal of chemical modifications in the chromatin. Epigenetic genes have been reported to be acetylated in breast cancer cell lines or breast tumors and most of them play critical roles in cell-cycle progression, differentiation, apoptosis, and autophagy [7,8,9,10,11]
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