BACKGROUND: Cytosolic Deacetylase HDAC6 is involved in the autophagy degradation
pathway of malformed proteins, an important survival mechanism in cancer cells. We
evaluated modulation of autophagy-related proteins and cell death by the HDAC6-selective
inhibitor C1A.
METHODS: Autophagy substrates (LC3 and p62 proteins) and endoplasmic reticulum (ER)
stress phenotype were determined. Caspase 3/7 activation and cellular proliferation assays
were used to assess consequences of autophagy modulation.
RESULTS: C1A potently resolved autophagy substrates induced by 3-MA and chloroquine.
The mechanism of autophagy inhibition by HDAC6 genetic knockout or C1A treatment
was consistent with abrogation of autophagosome-lysosome fusion, and decrease of Myc
protein. C1A alone or combined with the proteasome inhibitor, bortezomib, enhanced cell
death in malignant cells demonstrating the complementary roles of the proteasome and
autophagy pathways for clearing malformed proteins. Myc positive neuroblastoma, KRAS
positive colorectal cancer and multiple myeloma cells showed marked cell growth
inhibition in response to HDAC6 inhibitors. Finally, growth of neuroblastoma xenografts
was arrested in vivo by single agent C1A, while combination with bortezomib slowed the
growth of colorectal cancer xenografts.
CONCLUSIONS: C1A resolves autophagy substrates in malignant cells and induces cell
death, warranting its use for in vivo pre-clinical autophagy research.