HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms

Can Küçük, Xiaozhou Hu, Javeed Iqbal, Philippe Gaulard, David L Klinkebiel, Adam Cornish, Bhavana J Dave, Wing C. Chan

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)49-55
Number of pages7
JournalAmerican Journal of Pathology
Volume182
Issue number1
DOIs
StatePublished - Jan 1 2013

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Tumor Suppressor Genes
Natural Killer Cells
Neoplasms
Cytosine
Guanine
Islands
Phosphates
G2 Phase Cell Cycle Checkpoints
Cell Line
Null Lymphocytes
Ubiquitin-Protein Ligases
Interleukin-2
Homeostasis
Clone Cells
Alleles
Apoptosis
Biopsy
Polymerase Chain Reaction
Messenger RNA

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms. / Küçük, Can; Hu, Xiaozhou; Iqbal, Javeed; Gaulard, Philippe; Klinkebiel, David L; Cornish, Adam; Dave, Bhavana J; Chan, Wing C.

In: American Journal of Pathology, Vol. 182, No. 1, 01.01.2013, p. 49-55.

Research output: Contribution to journalArticle

Küçük, Can ; Hu, Xiaozhou ; Iqbal, Javeed ; Gaulard, Philippe ; Klinkebiel, David L ; Cornish, Adam ; Dave, Bhavana J ; Chan, Wing C. / HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms. In: American Journal of Pathology. 2013 ; Vol. 182, No. 1. pp. 49-55.
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