Heat shock protein 90 (HSP90) is a
molecular chaperone that supports stability of client
proteins. We found that HSP90 was cleaved to 55 kDa
protein after treatment with
histone deacetylase (
HDAC) inhibitors including
suberoylanilide hydroxamic acid (SAHA) in several
leukemia cell lines. We further analyzed molecular changes induced by SAHA in K562 cells. The SAHA-induced cleavage of HSP90 was blocked by a pan-
caspase inhibitor,
z-VAD-fmk, implying that the process is dependent on
caspase activity. However, the experiments using antagonistic and agonistic Fas
antibodies revealed that the cleavage of HSP90 was not dependent on Fas signaling. SAHA induced generation of
reactive oxygen species (ROS), and the cleavage of HSP90 was blocked by a ROS scavenger N-acetylcystein (NAC). We also confirmed that
hydrogen peroxide (H2O2) induced cleavage of HSP90 in a similar manner.
Caspase 2, 3, 4, 6, 8, and 10 were activated by treatment with SAHA, and the activities were reduced by the pretreatment of NAC. Treatment of the cells with
caspase 10 inhihitor, but not other inhibitors of
caspases activated by SAHA, prevented cleavage of HSP90 by SAHA. SAHA-induced ROS generation and HSP90 cleavage were dependent on newly synthesized unknown
proteins. Taken together, our results suggest that the cleavage of HSP90 by SAHA is mediated by ROS generation and
caspase 10 activation. HSP90 cleavage may provide an additional mechanism involved in anti-
cancer effects of
HDAC inhibitors.