Loss of Sirtuin 1 Alters the Secretome of Breast Cancer Cells by Impairing Lysosomal Integrity

Dev Cell. 2019 May 6;49(3):393-408.e7. doi: 10.1016/j.devcel.2019.03.011. Epub 2019 Apr 11.


The NAD+-dependent deacetylase Sirtuin 1 (SIRT1) is down-regulated in triple-negative breast cancer. To determine the mechanistic basis by which reduced SIRT1 expression influences processes related to certain aggressive cancers, we examined the consequences of depleting breast cancer cells of SIRT1. We discovered that reducing SIRT1 levels decreased the expression of one particular subunit of the vacuolar-type H+ ATPase (V-ATPase), which is responsible for proper lysosomal acidification and protein degradation. This impairment in lysosomal function caused a reduction in the number of multi-vesicular bodies (MVBs) targeted for lysosomal degradation and resulted in larger MVBs prior to their fusing with the plasma membrane to release their contents. Collectively, these findings help explain how reduced SIRT1 expression, by disrupting lysosomal function and generating a secretome comprising exosomes with unique cargo and soluble hydrolases that degrade the extracellular matrix, can promote processes that increase breast-cancer-cell survival and invasion.

Keywords: cancer; cathepsin; deacetylation; exosomes; extracellular vesicles; lysosome; multi-vesicular body; secretome; sirtuin; vacuolar-type H(+) ATPase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / physiology
  • Exosomes / metabolism
  • Female
  • Homeostasis
  • Humans
  • Lysosomes / metabolism*
  • Multivesicular Bodies / metabolism
  • Neoplasm Invasiveness
  • Sirtuin 1 / deficiency*
  • Sirtuin 1 / metabolism
  • Vacuolar Proton-Translocating ATPases / metabolism


  • SIRT1 protein, human
  • Sirtuin 1
  • Vacuolar Proton-Translocating ATPases