CLU blocks HDACI-mediated killing of neuroblastoma.
Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation.
Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Chitra
C
Subramanian
Jason A
JA
Jarzembowski
Sonja M
SM
Halsey
Rork
R
Kuick
Anthony W
AW
Opipari
Valerie P
VP
Castle
Roland P S
RP
Kwok
D000107:Acetylation / Q000187:drug effects; D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051152:Clusterin / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D000072200:Ku Autoantigen; D009447:Neuroblastoma / Q000473:pathology* / Q000503:physiopathology; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000502:physiology
D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D051152:Clusterin; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D051028:bcl-2-Associated X Protein; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen