HACE1 Is a Tumor Suppressor Gene Candidate in Natural Killer Cell Neoplasms

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.

How I treat NK/T-cell lymphomas

“…[26][27][28] Based on the observations that 6q21 is frequently deleted, [26][27][28][29] genes residing in this region, including FOXO3, PRDM1, and HACE1, have been shown to be putative tumor-suppressor genes. [30][31][32] The gene PRDM1 (alias BLIMP1) is particularly interesting because it regulates the maturation, homeostasis, and proliferation of NK cells. 33 Gene expression profiling has shown patterns different from normal NK cells and other T-cell lymphomas.…”

Aspects moléculaires des lymphomes T périphériques (2)

“…Des mutations faux sens de FOXO3 ont en effet été identifiées chez 7 % des patients avec lymphomes NK/T [24]. Enfin, le gène HACE1 (HECT E3 ubiquitin ligase) est sous-exprimé dans des tumeurs primaires et des lignées de lymphomes NK/T [10,25]. HACE1 code une E3 ubiquitine ligase et agit comme un gène suppresseur de tumeur dans les tumeurs de Wilms 2 [26,27].…”

“…HACE1 est délété de façon monoallélique dans 2/3 des lignées de lymphomes NK/T et 1/3 des tumeurs primaires. Il est hyperméthylé sur l'autre allèle, dans la plupart des cas [25].…”

VIII. New markers in peripheral T‐cell lymphomas: more entities or more confusion?

“…The 6q deleted region contains four candidate tumour suppressor genes, that is PRDM1, ATG5, AIM1 and HACE1, with decreased expression confirmed in NKTCLs [9]. As several of these genes appear to be inactivated through methylation, the potential use of demethylating agents in refractory patients might be suggested.…”