Page 100 - ebook

[A. Biochemistry/Molecular Biology] A-50

Histone deacetylase inhibitor- and proteasome inhibitor-

mediated cleavage of HSP90β induces cell apoptosis and

suppresses cell growth

Sangkyu Park¹, Jae-Hyung Jeon², Jeong-A Park¹, Jun-Kyu Choi², Ye-Ram Choi², Ha-Eun Shin²,

Younghee Lee¹,²*

¹Biotechnology Research Institute, Chungbuk National University, Chungju 28644, Korea, ²Department of

Biochemistry, Chungbuk National University, Chungju 28644, Korea

HSP90 is one of the molecular chaperones which contributes to protein stability in most living organisms. Previously,
we found that HSP90 cleavage occurred when histone deacetylase inhibitor or proteasome inhibitor were treated

in leukemia cells. In this study, we found that HSP90 cleavage of HSP90 was induced by treatment of SAHA and
MG132 in 6 out of 16 solid tumor cell lines. To investigate the effects of the cleavage of HSP90 on cells, we predicted

the potential cleavage site of HSP90 and established mutant constructs. Through in vitro cleavage assay using
recombinant proteins, we found that the 294th aspartic acid residue of the HSP90β was mainly cleaved by caspase

10. We then established K562 and Mia-PaCa-2 mutant cell lines expressing HSP90β D294A using retroviral system.
The cells showed reduced cleavage of HSP90 by treatment of SAHA and MG132 compared with the K562 and Mia-

PaCa-2 cell lines expressing HSP90β WT. Furthermore, cell growth was increased and cell apoptosis was reduced by
HSP90β D294A expression in SAHA- and MG132-treated condition. Therefore, we suggest that the HSP90 cleavage

widely occurs in several cell lines, and the cleavage of HSP90 may be one of the mechanisms involved in the anti-
tumor effects of anti-cancer drugs.