HACE1 is a putative tumor suppressor gene in B-cell lymphomagenesis and is down-regulated by both deletion and epigenetic alterations.
HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1, HACE1, located on chromosome 6q, encodes an E3 ubiquitin ligase and is downregulated in many human tumors. Here, we report HACE1 as a candidate tumor suppressor gene down-regulated by a combination of deletion and epigenetic mechanisms. HACE1 deletions were observed in 40% of B-cell lymphoma tumors. Hypermethylation of the HACE1 promoter CpG177 island was found in 60% (68/111) of cases and in all tested B-cell lymphoma lines. Using HDAC inhibitors, we observed predominantly inactive chromatin conformation (methylated H3 histones H3K9me2) in HACE1 gene promoter region. We demonstrated in Ramos and Raji cells that down-regulation of HACE1 expression was associated with a significant decrease in apoptosis and an accumulation of cells in the S and G2/M phases. Our experiments indicate that HACE1 can act as a haploinsufficient tumor suppressor gene in most B-cell lymphomas and can be downregulated by deacetylation of its promoter region chromatin, which makes HACE1 a potential target for HDAC inhibitors.
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France. Electronic address: bouzelfi.a@gmail.com.
Abdelilah
A
Bouzelfen
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Marion
M
Alcantara
INSERM U1079, Faculty of Medecine of Rouen, iRiB, France.
Hafid
H
Kora
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Jean-Michel
JM
Picquenot
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Philippe
P
Bertrand
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Marie
M
Cornic
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Sylvain
S
Mareschal
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Elodie
E
Bohers
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Catherine
C
Maingonnat
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Philippe
P
Ruminy
INSERM U905, Faculty of medecine of Rouen, iRiB, France.
Sahil
S
Adriouch
INSERM U905, Faculty of medecine of Rouen, iRiB, France.
Olivier
O
Boyer
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Sydney
S
Dubois
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Christian
C
Bastard
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Hervé
H
Tilly
INSERM U1079, Faculty of Medecine of Rouen, iRiB, France.
Jean-Baptiste
JB
Latouche
Henri Becquerel Center, INSERM U918, Institut de Recherche et d'Innovation Biomédicale (iRiB) Rouen, France.
Fabrice
F
Jardin
D000107:Acetylation; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation / Q000235:genetics*; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics*; D011401:Promoter Regions, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D056572:Histone Deacetylase Inhibitors; C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases
Deletions; Epigenetic; HDAC inhibitors; Lymphoma; Tumor suppressor gene