Ubiquitin B: an essential mediator of trichostatin A-induced tumor-selective killing in human cancer cells.
Although histone deacetylase inhibitors (HDACis) are emerging as a new class of anticancer agents, the mechanism of tumor-selective killing by HDACi is not well understood. We used suppression of mortality by antisense rescue technique (SMART) to screen the key genes responsible for the tumor-selective killing by trichostatin A (TSA). Twenty-four genes were identified, the most significant of which was ubiquitin B (UbB). The expression of UbB was selectively upregulated by TSA in tumor cells, but not non-malignant cells. Further observation indicated that TSA induced a substantial dissipation of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, and proteolytic cleavage of caspases-3/9 in HeLa cells, which was apparently mediated by ubiquitylation and the subsequent degradation of mitochondrial membrane proteins including BCL-2 and MCL-1. In contrast, knockdown of UbB expression inhibited the TSA-induced apoptotic cascade by abolishing TSA-induced ubiquitylation and the subsequent degradation of mitochondrial membrane proteins. Furthermore, apicidine, another HDACi, exhibited activity similar to that of TSA. Interestingly, TSA induced UbB-dependent proteasomal degradation of BCR-ABL fusion protein in K562 leukemic cells. Thus, our findings highlight the essential role of UbB and UbB-dependent proteasomal protein degradation in HDACi-induced tumor selectivity. The mechanism provides a novel starting point for dissecting the molecular mechanism underlying the tumor selectivity of HDACi.
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
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P
Wu
Y
Y
Tian
G
G
Chen
B
B
Wang
L
L
Gui
L
L
Xi
X
X
Ma
Y
Y
Fang
T
T
Zhu
D
D
Wang
L
L
Meng
G
G
Xu
S
S
Wang
D
D
Ma
J
J
Zhou
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination; D015854:Up-Regulation
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C479419:UBB protein, human; D025801:Ubiquitin; C012589:trichostatin A; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9