TY - JOUR
T1 - HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms
AU - Küçük, Can
AU - Hu, Xiaozhou
AU - Iqbal, Javeed
AU - Gaulard, Philippe
AU - Klinkebiel, David
AU - Cornish, Adam
AU - Dave, Bhavana J.
AU - Chan, Wing C.
N1 - Funding Information:
Supported by Lymphoma SPORE P50CA136411-01 (NCI) (W.C.C. and J.I.) and a grant from the National Cancer Institute ( 5U01/CA114778 ).
PY - 2013/1
Y1 - 2013/1
N2 - HACE1 is an E3 ubiquitin ligase located in 6q21, the genomic region frequently deleted in natural killer (NK) cell malignancies. Here, we report HACE1 as a candidate tumor suppressor gene silenced through a combination of deletion and cytosine phosphate guanine island hypermethylation. We detected deletion of HACE1 in malignant NK cell lines (6 of 9, 67%) and primary biopsies (5 of 15, 33%) by quantitative PCR, with most of the specimen showing cytosine phosphate guanine island hypermethylation in the remaining allele, leading to low mRNA transcription. The ectopic expression of HACE1 in an HACE1-null NK cell line led to apoptosis and G2/M cell cycle arrest. Moreover, HACE1 expression was up-regulated in IL-2-activated normal NK cells and NK cells cocultured with an engineered NK cell target, K562 Clone 9.mbIL21, suggesting its role in the regulation of NK cell homeostasis. In conclusion, HACE1 is another potent tumor suppressor gene located within the 6q21 region, and loss of function of multiple tumor suppressor genes within 6q21 may be a critical determinant of NK cell lymphomagenesis.
AB - HACE1 is an E3 ubiquitin ligase located in 6q21, the genomic region frequently deleted in natural killer (NK) cell malignancies. Here, we report HACE1 as a candidate tumor suppressor gene silenced through a combination of deletion and cytosine phosphate guanine island hypermethylation. We detected deletion of HACE1 in malignant NK cell lines (6 of 9, 67%) and primary biopsies (5 of 15, 33%) by quantitative PCR, with most of the specimen showing cytosine phosphate guanine island hypermethylation in the remaining allele, leading to low mRNA transcription. The ectopic expression of HACE1 in an HACE1-null NK cell line led to apoptosis and G2/M cell cycle arrest. Moreover, HACE1 expression was up-regulated in IL-2-activated normal NK cells and NK cells cocultured with an engineered NK cell target, K562 Clone 9.mbIL21, suggesting its role in the regulation of NK cell homeostasis. In conclusion, HACE1 is another potent tumor suppressor gene located within the 6q21 region, and loss of function of multiple tumor suppressor genes within 6q21 may be a critical determinant of NK cell lymphomagenesis.
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U2 - 10.1016/j.ajpath.2012.09.012
DO - 10.1016/j.ajpath.2012.09.012
M3 - Article
C2 - 23142381
AN - SCOPUS:84871333633
SN - 0002-9440
VL - 182
SP - 49
EP - 55
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -