PCDH17 functions as a common tumor suppressor gene in acute leukemia and its transcriptional downregulation is mediated primarily by aberrant histone acetylation, not DNA methylation.

Abstract	We recently reported that methylation of PCDH17 gene is found in 30% of children with B-cell precursor acute lymphoblastic leukemia (ALL), and is significantly correlated to event-free or overall survival. We here evaluated PCDH17 mRNA expression in pediatric acute myeloid leukemia (AML) and ALL. PCDH17 mRNA expression levels in children with ALL/AML were lower than those in healthy counterparts. We next elucidated the mechanism underlying down-regulation of PCDH17 mRNA, using myeloid and lymphoid leukemic cell lines. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) resulted in restoration of PCDH17 mRNA expression and growth inhibition in K562, HL60, REH, and RCH-ACV cell lines. Upregulation of PCDH17 mRNA expression resulted from histone H3 acetylation. Knockdown of the PCDH17 gene, caused by transduction of PCDH17-targeted shRNA, significantly enhanced the proliferation of KU812 cells. Meanwhile, overexpression of PCDH17 via retroviral-particle transfection substantially inhibited the growth of Kasumi1 cells. The fold-increase in PCDH17 mRNA expression mediated by 5-azacytidine, an inhibitor of DNA methyltransferase, was fundamentally lower than that produced by TSA. In conclusion, our results suggest that PCDH17 gene functions as a common tumor suppressor gene in leukemic cells, and that histone deacetylase inhibitors re-express PCDH17 mRNA to a greater extent than demethylation reagents.
Authors	Le Thanh Nha Uyen, Yuji Amano, Lika'a Fasih Y Al-Kzayer, Noriko Kubota, Jun Kobayashi, Yozo Nakazawa, Kenichi Koike, Kazuo Sakashita
Journal	International journal of hematology (Int J Hematol) Vol. 111 Issue 3 Pg. 451-462 (Mar 2020) ISSN: 1865-3774 [Electronic] Japan
PMID	31865541 (Publication Type: Journal Article)
Chemical References	Cadherins Histones PCDH17 protein, human RNA, Messenger
Topics	Acetylation Acute Disease Cadherins (genetics, physiology) Cell Line, Tumor Cells, Cultured Child, Preschool DNA Methylation Down-Regulation Gene Expression Genes, Tumor Suppressor Histones (metabolism) Humans Leukemia, Myeloid, Acute (genetics) Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics) RNA, Messenger (genetics, metabolism) Transcription, Genetic

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