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Erschienen in: International Journal of Hematology 3/2020

01.03.2020 | Original Article

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

verfasst von: Le Thanh Nha Uyen, Yuji Amano, Lika’a Fasih Y. Al-Kzayer, Noriko Kubota, Jun Kobayashi, Yozo Nakazawa, Kenichi Koike, Kazuo Sakashita

Erschienen in: International Journal of Hematology | Ausgabe 3/2020

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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.
Literatur
1.
Zurück zum Zitat Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007;115:138–45. Review. Erratum in: Environ Health Perspect. 2010;118:A380. Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007;115:138–45. Review. Erratum in: Environ Health Perspect. 2010;118:A380.
2.
Zurück zum Zitat Masetti R, Serravalle S, Biagi C, Pession A. The role of HDACs inhibitors in childhood and adolescence acute leukemias. J Biomed Biotechnol. 2011;2011:148046.CrossRef Masetti R, Serravalle S, Biagi C, Pession A. The role of HDACs inhibitors in childhood and adolescence acute leukemias. J Biomed Biotechnol. 2011;2011:148046.CrossRef
3.
Zurück zum Zitat Pession A, Rondelli R, Basso G, Rizzari C, Testi AM, Fagioli F, et al. AML Strategy & Study Committee of the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP). Treatment and long-term results in children with acute myeloid leukaemia treated according to the AIEOP AML protocols. Leukemia. 2005;19:2043–53. Pession A, Rondelli R, Basso G, Rizzari C, Testi AM, Fagioli F, et al. AML Strategy & Study Committee of the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP). Treatment and long-term results in children with acute myeloid leukaemia treated according to the AIEOP AML protocols. Leukemia. 2005;19:2043–53.
4.
Zurück zum Zitat Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. 2004;350:1535–48.CrossRef Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. 2004;350:1535–48.CrossRef
5.
Zurück zum Zitat Abrahamsson J, Clausen N, Gustafsson G, Hovi L, Jonmundsson G, Zeller B, et al. Improved outcome after relapse in children with acute myeloid leukaemia. Br J Haematol. 2007;136:229–36.CrossRef Abrahamsson J, Clausen N, Gustafsson G, Hovi L, Jonmundsson G, Zeller B, et al. Improved outcome after relapse in children with acute myeloid leukaemia. Br J Haematol. 2007;136:229–36.CrossRef
6.
Zurück zum Zitat Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. 2010;28:2339–477.CrossRef Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. 2010;28:2339–477.CrossRef
7.
Zurück zum Zitat Galm O, Herman JG, Baylin SB. The fundamental role of epigenetics in hematopoietic malignancies. Blood Rev. 2006;20:1–13.CrossRef Galm O, Herman JG, Baylin SB. The fundamental role of epigenetics in hematopoietic malignancies. Blood Rev. 2006;20:1–13.CrossRef
8.
Zurück zum Zitat Hattori N, Ushijima T. Compendium of aberrant DNA methylation and histone modifications in cancer. Biochem Biophys Res Commun. 2014;455:3–9.CrossRef Hattori N, Ushijima T. Compendium of aberrant DNA methylation and histone modifications in cancer. Biochem Biophys Res Commun. 2014;455:3–9.CrossRef
9.
Zurück zum Zitat Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.CrossRef Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.CrossRef
10.
Zurück zum Zitat Xiao L, Huang Y, Zhen R, Chiao J, Liu D, Ma X. Deficient histone acetylation in acute leukemia and the correction by an isothiocyanate. Acta Haematol. 2010;123:71–6.CrossRef Xiao L, Huang Y, Zhen R, Chiao J, Liu D, Ma X. Deficient histone acetylation in acute leukemia and the correction by an isothiocyanate. Acta Haematol. 2010;123:71–6.CrossRef
11.
Zurück zum Zitat Chen C, Zhao M, Yin N, He B, Wang B, Yuan Y. Abnormal histone acetylation and methylation levels in esophageal squamous cell carcinomas. Cancer Invest. 2011;29:548–56.CrossRef Chen C, Zhao M, Yin N, He B, Wang B, Yuan Y. Abnormal histone acetylation and methylation levels in esophageal squamous cell carcinomas. Cancer Invest. 2011;29:548–56.CrossRef
12.
Zurück zum Zitat Duchmann M, Itzykson R. Clinical update on hypomethylating agents. Int J Hematol. 2019;110:161–9.CrossRef Duchmann M, Itzykson R. Clinical update on hypomethylating agents. Int J Hematol. 2019;110:161–9.CrossRef
13.
Zurück zum Zitat Kim SY, Yasuda S, Tanaka H, Yamagata K, Kim H. Non-clustered protocadherin. Cell Adh Migr. 2011;5:97–105.CrossRef Kim SY, Yasuda S, Tanaka H, Yamagata K, Kim H. Non-clustered protocadherin. Cell Adh Migr. 2011;5:97–105.CrossRef
14.
Zurück zum Zitat Frank M, Kemler R. Protocadherins. Curr Opin Cell Biol. 2002;14:557–62.CrossRef Frank M, Kemler R. Protocadherins. Curr Opin Cell Biol. 2002;14:557–62.CrossRef
15.
Zurück zum Zitat Imoto I, Izumi H, Yokoi S, Hosoda H, Shibata T, Hosoda F, et al. Frequent silencing of the candidate tumor suppressor PCDH20 by epigenetic mechanism in non–small-cell lung cancers. Cancer Res. 2006;66:4617–26.CrossRef Imoto I, Izumi H, Yokoi S, Hosoda H, Shibata T, Hosoda F, et al. Frequent silencing of the candidate tumor suppressor PCDH20 by epigenetic mechanism in non–small-cell lung cancers. Cancer Res. 2006;66:4617–26.CrossRef
16.
Zurück zum Zitat Sui X, Wang D, Geng S, Zhou G, He C, Hu X. Methylated promoters of genes encoding protocadherins as a new cancer biomarker family. Mol Biol Rep. 2012;39:1105–11.CrossRef Sui X, Wang D, Geng S, Zhou G, He C, Hu X. Methylated promoters of genes encoding protocadherins as a new cancer biomarker family. Mol Biol Rep. 2012;39:1105–11.CrossRef
17.
Zurück zum Zitat Wang KH, Liu HW, Lin SR, Ding DC, Chu TY. Field methylation silencing of the protocadherin 10 gene in cervical carcinogenesis as a potential specific diagnostic test from cervical scrapings. Cancer Sci. 2009;100:2175–80.CrossRef Wang KH, Liu HW, Lin SR, Ding DC, Chu TY. Field methylation silencing of the protocadherin 10 gene in cervical carcinogenesis as a potential specific diagnostic test from cervical scrapings. Cancer Sci. 2009;100:2175–80.CrossRef
18.
Zurück zum Zitat Ying J, Gao Z, Li H, Srivastava G, Murray PG, Goh HK, et al. Frequent epigenetic silencing of protocadherin 10 by methylation in multiple haematologic malignancies. Br J Haematol. 2007;136:829–32.CrossRef Ying J, Gao Z, Li H, Srivastava G, Murray PG, Goh HK, et al. Frequent epigenetic silencing of protocadherin 10 by methylation in multiple haematologic malignancies. Br J Haematol. 2007;136:829–32.CrossRef
19.
Zurück zum Zitat Yu J, Koujak S, Nagase S, Li C, Su T, Wang X, et al. PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer. Oncogene. 2008;27:4657–65.CrossRef Yu J, Koujak S, Nagase S, Li C, Su T, Wang X, et al. PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer. Oncogene. 2008;27:4657–65.CrossRef
20.
Zurück zum Zitat Ying J, Li H, Seng TJ, Langford C, Srivastava G, Tsao S, et al. Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation. Oncogene. 2006;25:1070–80.CrossRef Ying J, Li H, Seng TJ, Langford C, Srivastava G, Tsao S, et al. Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation. Oncogene. 2006;25:1070–80.CrossRef
21.
Zurück zum Zitat Yu B, Yang H, Zhang C, Wu Q, Shao Y, Zhang J, et al. High-resolution melting analysis of PCDH10 methylation levels in gastric, colorectal and pancreatic cancers. Neoplasma. 2010;57:247–52.CrossRef Yu B, Yang H, Zhang C, Wu Q, Shao Y, Zhang J, et al. High-resolution melting analysis of PCDH10 methylation levels in gastric, colorectal and pancreatic cancers. Neoplasma. 2010;57:247–52.CrossRef
22.
Zurück zum Zitat Yu J, Cheng YY, Tao Q, Cheung KF, Lam CN, Geng H, et al. Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer. Gastroenterology. 2009;136:640–51.CrossRef Yu J, Cheng YY, Tao Q, Cheung KF, Lam CN, Geng H, et al. Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer. Gastroenterology. 2009;136:640–51.CrossRef
23.
Zurück zum Zitat Costa VL, Henrique R, Danielsen SA, Eknaes M, Patrício P, Morais A, et al. TCF21 and PCDH17 methylation: an innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics. 2011;6:1120–30.CrossRef Costa VL, Henrique R, Danielsen SA, Eknaes M, Patrício P, Morais A, et al. TCF21 and PCDH17 methylation: an innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics. 2011;6:1120–30.CrossRef
24.
Zurück zum Zitat Haruki S, Imoto I, Kozaki K-i, Matsui T, Kawachi H, Komatsu S, et al. Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous-cell carcinoma. Carcinogenesis. 2010;31:1027–36.CrossRef Haruki S, Imoto I, Kozaki K-i, Matsui T, Kawachi H, Komatsu S, et al. Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous-cell carcinoma. Carcinogenesis. 2010;31:1027–36.CrossRef
25.
Zurück zum Zitat Hu X, Sui X, Li L, Huang X, Rong R, Su X, et al. Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol. 2013;229:62–73.CrossRef Hu X, Sui X, Li L, Huang X, Rong R, Su X, et al. Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol. 2013;229:62–73.CrossRef
26.
Zurück zum Zitat Lin YL, Xie PG, Wang L, Ma JG. Aberrant methylation of protocadherin 17 and its clinical significance in patients with prostate cancer after radical prostatectomy. Med Sci Monit. 2014;20:1376–82.CrossRef Lin YL, Xie PG, Wang L, Ma JG. Aberrant methylation of protocadherin 17 and its clinical significance in patients with prostate cancer after radical prostatectomy. Med Sci Monit. 2014;20:1376–82.CrossRef
27.
Zurück zum Zitat Wang XB, Lin YL, Li ZG, Ma JH, Li J, Ma JG. Protocadherin 17 promoter methylation in tumour tissue from patients with bladder transitional cell carcinoma. J Int Med Res. 2014;42:292–9.CrossRef Wang XB, Lin YL, Li ZG, Ma JH, Li J, Ma JG. Protocadherin 17 promoter methylation in tumour tissue from patients with bladder transitional cell carcinoma. J Int Med Res. 2014;42:292–9.CrossRef
28.
Zurück zum Zitat He Y, Wang Z, Liu C, Gong Z, Li Y, Lu T, Hu G. Protocadherin 17 is a tumor suppressor and is frequently methylated in nasopharyngeal carcinoma. Cancer Manag Res. 2019;11:1601–13.CrossRef He Y, Wang Z, Liu C, Gong Z, Li Y, Lu T, Hu G. Protocadherin 17 is a tumor suppressor and is frequently methylated in nasopharyngeal carcinoma. Cancer Manag Res. 2019;11:1601–13.CrossRef
29.
Zurück zum Zitat Uyen LTN, Sakashita K, Al-Kzayer LF, Nakazawa Y, Kurata T, Koike K. Aberrant methylation of protocadherin 17 and its prognostic value in pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer. 2017;64. Uyen LTN, Sakashita K, Al-Kzayer LF, Nakazawa Y, Kurata T, Koike K. Aberrant methylation of protocadherin 17 and its prognostic value in pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer. 2017;64.
30.
Zurück zum Zitat Sakashita K, Koike K, Kinoshita T, Shiohara M, Kamijo T, Taniguchi S, et al. Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. J Clin Invest. 2001;108:1195–204.CrossRef Sakashita K, Koike K, Kinoshita T, Shiohara M, Kamijo T, Taniguchi S, et al. Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. J Clin Invest. 2001;108:1195–204.CrossRef
31.
Zurück zum Zitat Zhao XY, Sakashita K, Kamijo T, Hidaka E, Sugane K, Kubota T, et al. Granulocyte–macrophage colony-stimulating factor induces de novo methylation of the p15 CpG island in hematopoietic cells. Cytokine. 2005;31:203–12.CrossRef Zhao XY, Sakashita K, Kamijo T, Hidaka E, Sugane K, Kubota T, et al. Granulocyte–macrophage colony-stimulating factor induces de novo methylation of the p15 CpG island in hematopoietic cells. Cytokine. 2005;31:203–12.CrossRef
32.
Zurück zum Zitat Al-Kzayer LF, Sakashita K, Matsuda K, Al-Hadad SA, Al-Jadiry MF, Abed WM, et al. Genetic evaluation of childhood acute lymphoblastic leukemia in Iraq using FTA cards. Pediatr Blood Cancer. 2012;59:461–7.CrossRef Al-Kzayer LF, Sakashita K, Matsuda K, Al-Hadad SA, Al-Jadiry MF, Abed WM, et al. Genetic evaluation of childhood acute lymphoblastic leukemia in Iraq using FTA cards. Pediatr Blood Cancer. 2012;59:461–7.CrossRef
33.
Zurück zum Zitat Ogawa M, Sakashita K, Zhao XY, Hayakawa A, Kubota T, Koike K. Analysis of histone modification around the CpG island region of the p15 gene in acute myeloblastic leukemia. Leuk Res. 2007;31:611–21.CrossRef Ogawa M, Sakashita K, Zhao XY, Hayakawa A, Kubota T, Koike K. Analysis of histone modification around the CpG island region of the p15 gene in acute myeloblastic leukemia. Leuk Res. 2007;31:611–21.CrossRef
34.
Zurück zum Zitat Xu ZJ, Ma JC, Zhou JD, Wen XM, Yao DM, Zhang W, et al. Reduced protocadherin17 expression in leukemia stem cells: the clinical and biological effect in acute myeloid leukemia. J Transl Med. 2019;17:102.CrossRef Xu ZJ, Ma JC, Zhou JD, Wen XM, Yao DM, Zhang W, et al. Reduced protocadherin17 expression in leukemia stem cells: the clinical and biological effect in acute myeloid leukemia. J Transl Med. 2019;17:102.CrossRef
35.
Zurück zum Zitat Yin X, Xiang T, Mu J, Mao H, Li L, Huang X, et al. Protocadherin 17 functions as a tumor suppressor suppressing Wnt/β-catenin signaling and cell metastasis and is frequently methylated in breast cancer. Oncotarget. 2016;7:51720–32.PubMedPubMedCentral Yin X, Xiang T, Mu J, Mao H, Li L, Huang X, et al. Protocadherin 17 functions as a tumor suppressor suppressing Wnt/β-catenin signaling and cell metastasis and is frequently methylated in breast cancer. Oncotarget. 2016;7:51720–32.PubMedPubMedCentral
Metadaten
Titel
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
verfasst von
Le Thanh Nha Uyen
Yuji Amano
Lika’a Fasih Y. Al-Kzayer
Noriko Kubota
Jun Kobayashi
Yozo Nakazawa
Kenichi Koike
Kazuo Sakashita
Publikationsdatum
01.03.2020
Verlag
Springer Singapore
Erschienen in
International Journal of Hematology / Ausgabe 3/2020
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-019-02799-4

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