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.
Wu
P
P
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
Tian
Y
Y
Chen
G
G
Wang
B
B
Gui
L
L
Xi
L
L
Ma
X
X
Fang
Y
Y
Zhu
T
T
Wang
D
D
Meng
L
L
Xu
G
G
Wang
S
S
Ma
D
D
Zhou
J
J
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