Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis.
Aberrant acetylation has been strongly linked to tumorigenesis, and the modulation of acetylation through targeting histone deacetylases (HDACs) is gathering increasing pace as a viable therapeutic strategy. A genome-wide loss-of-function screen identified HR23B, which shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDAC inhibitor-induced apoptosis. HR23B also governs tumor cell sensitivity to drugs that act directly on the proteasome. The level of HR23B influences the response of tumor cells to HDAC inhibitors, and HR23B is found at high levels in cutaneous T cell lymphoma in situ, a malignancy that responds favorably to HDAC inhibitor-based therapy. These results suggest that deregulated proteasome activity contributes to the anticancer activity of HDAC inhibitors.
Fotheringham
Susan
S
Laboratory of Cancer Biology, Department of Clinical Pharmacology, Medical Sciences Division, University of Oxford, Old Road Campus Research Building, Oxford, UK.
Epping
Mirjam T
MT
Stimson
Lindsay
L
Khan
Omar
O
Wood
Victoria
V
Pezzella
Francesco
F
Bernards
René
R
La Thangue
Nicholas B
NB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D012878:Skin Neoplasms / Q000378:metabolism; D013379:Substrate Specificity
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C475578:Rad23a protein, mouse; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases