Suppression of SOX7 by DNA methylation and its tumor suppressor function in acute myeloid leukemia.
SOX7 belongs to the SOX (Sry-related high-mobility group [HMG] box) gene family, a group of transcription factors containing in common a HMG box domain. Its role in hematologic malignancies and, in particular, acute myeloid leukemia (AML) is completely unknown. Here, we showed that SOX7 expression was regulated by DNA hypermethylation in AML but not in acute lymphoblastic leukemia or normal bone marrow cells. In cell lines (KG1, ML2, and K562) and in primary CD34(+) AML samples, SOX7 expression could be induced by the DNA demethylating agent 5-aza-2'-deoxycytidine. Overexpression of SOX7 in K562 cells inhibited cell proliferation, with cell cycle delay in S/G2/M phases and reduced clonogenic activity. Apoptosis was unaffected. Ectopic expression of SOX7 in K562 and THP-1 cells, as well as primary CD33(+)CD34(+) AML cells, abrogated leukemia engraftment in xenogeneic transplantation. SOX7 expression inhibited the Wnt/β-catenin pathway through direct protein binding to β-catenin, and the antileukemia effects of SOX7 in THP-1 cells were significantly reduced by deletion of its β-catenin binding site. The results provided unequivocal evidence for a novel tumor suppressor role of SOX7 in AML via a negative modulatory effect on the Wnt/β-catenin pathway.
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
Cheuk Him
CH
Man
Leukaemia and Stem Cell Biology Laboratory, Department of Haematological Medicine, King's College London, London, United Kingdom;
Tsz Kan
TK
Fung
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
Haixia
H
Wan
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
Chae Yin
CY
Cher
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
August
A
Fan
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
Nelson
N
Ng
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
Christa
C
Ho
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; and.
Thomas S K
TS
Wan
Laboratory of Immunobiology, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.
Toshiyuki
T
Tanaka
Leukaemia and Stem Cell Biology Laboratory, Department of Haematological Medicine, King's College London, London, United Kingdom;
Chi Wai Eric
CW
So
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
Yok Lam
YL
Kwong
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
Anskar Y H
AY
Leung
D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000502:physiology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055760:SOXF Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D059467:Transcriptome
C484456:SOX7 protein, human; D055760:SOXF Transcription Factors