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Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL

発表形態:
原著論文
主要業績:
主要業績
単著・共著:
共著
発表年月:
2023年04月
DOI:
10.1182/bloodadvances.2022008362
会議属性:
指定なし
査読:
有り
リンク情報:

日本語フィールド

著者:
Kurahashi Y, Watanabe T, Yamamoto Y, Ureshino H, Kamachi K, Yoshida-Sakai N, Fukuda-Kurahashi Y, Yamashita S, Hattori N, Nakamura H, Kawaguchi A, Ushijima T, Sueoka E, Kimura S
題名:
Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL
発表情報:
Blood Adv 巻: 7 号: 8 ページ: 1545-1559
キーワード:
概要:
Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T cells caused by human T-cell lymphotropic virus type 1 (HTLV-1)-induced T-cell transformation. Following infection with HTLV-1, it takes several decades for HTLV-1 carriers to develop ATL. The prognosis of ATL remains poor despite several new agents are approved in the last few years. Recently, it has been noted that epigenetic abnormalities both DNA methylation and tri-methylation at histone H3Lys27 (H3K27me3) contribute to ATL leukemogenesis. Here, we investigated the effect of combination treatment with DNA demethylating agents (azacytidine (AZA), decitabine (DAC), and OR-2100 (OR21), which is silylated derivative of decitabine) and inhibitors of enhancer of zeste homolog 2 (EZH2) (EPZ-6438 and DS-3201b) which catalyze trimethylation of H3K27, in ATL. The combination of DAC and OR21 but not AZA with EZH inhibitors exhibited synergistic anti-ATL effects in vitro and in vivo concomitant with DNA demethylation and reduction of H3K27me3. The combination induced gene expression reprogramming. Dual-specificity phosphatase 5 (DUSP5), an ERK-specific phosphatase, was identified as a key molecule that mediated the inhibitory effect of combination treatment by inactivating the ERK signaling pathway. DUSP5 was downregulated by DNA methylation and H3K27me3 accumulation in the promoter region in HTLV-1-infected cells from ATL patients during ATL leukemogenesis. The present results demonstrate that dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth by restoring DUSP5, and the dual targeting of aberrant DNA and histone methylation is a feasible therapeutic approach for ATL.
抄録:

英語フィールド

Author:
Kurahashi Y, Watanabe T, Yamamoto Y, Ureshino H, Kamachi K, Yoshida-Sakai N, Fukuda-Kurahashi Y, Yamashita S, Hattori N, Nakamura H, Kawaguchi A, Ushijima T, Sueoka E, Kimura S
Title:
Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL
Announcement information:
Blood Adv Vol: 7 Issue: 8 Page: 1545-1559
An abstract:
Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T cells caused by human T-cell lymphotropic virus type 1 (HTLV-1)-induced T-cell transformation. Following infection with HTLV-1, it takes several decades for HTLV-1 carriers to develop ATL. The prognosis of ATL remains poor despite several new agents are approved in the last few years. Recently, it has been noted that epigenetic abnormalities both DNA methylation and tri-methylation at histone H3Lys27 (H3K27me3) contribute to ATL leukemogenesis. Here, we investigated the effect of combination treatment with DNA demethylating agents (azacytidine (AZA), decitabine (DAC), and OR-2100 (OR21), which is silylated derivative of decitabine) and inhibitors of enhancer of zeste homolog 2 (EZH2) (EPZ-6438 and DS-3201b) which catalyze trimethylation of H3K27, in ATL. The combination of DAC and OR21 but not AZA with EZH inhibitors exhibited synergistic anti-ATL effects in vitro and in vivo concomitant with DNA demethylation and reduction of H3K27me3. The combination induced gene expression reprogramming. Dual-specificity phosphatase 5 (DUSP5), an ERK-specific phosphatase, was identified as a key molecule that mediated the inhibitory effect of combination treatment by inactivating the ERK signaling pathway. DUSP5 was downregulated by DNA methylation and H3K27me3 accumulation in the promoter region in HTLV-1-infected cells from ATL patients during ATL leukemogenesis. The present results demonstrate that dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth by restoring DUSP5, and the dual targeting of aberrant DNA and histone methylation is a feasible therapeutic approach for ATL.


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