Abstract
HDAC6 is emerging as an important therapeutic target for cancer. We investigated mechanisms responsible for survival of tumor cells treated with a HDAC6 inhibitor. Expression of the 20 000 genes examined did not change following HDAC6 treatment in vivo. We found that HDAC6 inhibition led to an increase of AKT activation (P-AKT) in vitro, and genetic knockdown of HDAC6 phenocopied drug-induced AKT activation. The activation of AKT was not observed in PTEN null cells; otherwise, PTEN/PIK3CA expression per se did not predict HDAC6 inhibitor sensitivity. Interestingly, HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN (P-PTEN Ser380), which likely led to the increased P-AKT in cells that express PTEN. Synergy was observed with phosphatidylinositol 3'-kinases (PI3K) inhibitor treatment in vitro, accompanied by increased caspase 3/7 activity. Furthermore, combination of HDAC6 inhibitor with a PI3K inhibitor caused substantial tumor growth inhibition in vivo compared with either treatment alone, also detectable by Ki-67 immunostaining and 18F-FLT positron emission tomography (PET). In aggregate AKT activation appears to be a key survival mechanism for HDAC6 inhibitor treatment. Our findings indicate that dual inhibition of HDAC6 and P-AKT may be necessary to substantially inhibit growth of solid tumors.
Highlights
The acetylation status of protein lysines including that of histones is regulated by the reversible post-translational modification activities of histone deacetylases (HDACs; more accurately, lysine deacetylates) and histone acetyltransferases
HDAC6 was shown to deacetylase a diverse set of substrates involved in tumorigenesis including heat shock protein 90 (HSP90), α-tubulin, cortactin and peroxiredoxins, but, importantly, unlike other histone deacetylases, selective inhibition of HDAC6 is believed not be associated with severe toxicity and HDAC6 knockout does not lead to embryonic lethality.[2,3,4,5,6]
We further investigated whether C1A treatment activated AKT downstream substrates: hypoxia-inducible factor-1 α and glucose trasporter-1 (GLUT1).[21]
Summary
The acetylation status of protein lysines including that of histones is regulated by the reversible post-translational modification activities of histone deacetylases (HDACs; more accurately, lysine deacetylates) and histone acetyltransferases. Because these proteins are deregulated in cancer, there is a strong interest to inhibit their function. Loss of function can occur through mutation of PTEN, a tumor suppressor gene on chromosome 10q23, which encodes a dual-specificity lipid and protein phosphatase that negatively regulates AKT. Our results reveal a previously unknown mechanism by which AKT activation regulates survival following HDAC6 inhibitor treatment
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