KDM3A/Ets1/MCAM 轴促进横纹肌肉瘤的生长和转移特性。

Q2 Biochemistry, Genetics and Molecular Biology
Lays Martin Sobral, Marybeth Sechler, Janet K Parrish, Tyler S McCann, Kenneth L Jones, Joshua C Black, Paul Jedlicka
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引用次数: 0

摘要

横纹肌肉瘤(RMS)是儿童时期最常见的软组织恶性肿瘤。横纹肌肉瘤有两种主要的疾病亚型,融合阳性横纹肌肉瘤(FP-RMS)的预后通常比融合阴性横纹肌肉瘤(FN-RMS)差,部分原因是转移倾向较高。表观遗传机制近来已成为儿科癌症发病机制中的关键因素,也是潜在的新治疗漏洞。在本文中,我们发现表观遗传调节因子 KDM3A(Jumonji-dain 组蛋白去甲基化酶(JHDM)家族的成员)在 FN-RMS 和 FP-RMS 中都存在过表达,它能有效促进集落形成和跨内皮侵袭,并激活细胞生长、迁移和转移相关基因的表达。在机理研究中,我们证明这两种 RMS 亚型都利用了最近在尤文肉瘤中发现的 KDM3A/Ets1/MCAM 疾病促进轴,尤文肉瘤是另一种具有不同细胞和分子起源的侵袭性儿科癌症。我们进一步发现,在 FP-RMS 细胞中去除 KDM3A 可抑制肿瘤的体内生长和转移,而且 RMS 细胞对泛 JHDM 抑制剂 JIB-04 的集落生长抑制高度敏感。总之,我们的研究揭示了 KDM3A/Ets1/MCAM 轴在不同细胞和分子起源的小儿肉瘤中的重要作用,并确定了 RMS 中新的靶向脆弱性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.

KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy of childhood. RMS exists as two major disease subtypes, with oncofusion-positive RMS (FP-RMS) typically carrying a worse prognosis than oncofusion-negative RMS (FN-RMS), in part due to higher propensity for metastasis. Epigenetic mechanisms have recently emerged as critical players in the pathogenesis of pediatric cancers, as well as potential new therapeutic vulnerabilities. Herein, we show that the epigenetic regulator KDM3A, a member of the Jumonji-domain histone demethylase (JHDM) family, is overexpressed, potently promotes colony formation and transendothelial invasion, and activates the expression of genes involved in cell growth, migration and metastasis, in both FN-RMS and FP-RMS. In mechanistic studies, we demonstrate that both RMS subtypes utilize a KDM3A/Ets1/MCAM disease-promoting axis recently discovered in Ewing Sarcoma, another aggressive pediatric cancer of distinct cellular and molecular origin. We further show that KDM3A depletion in FP-RMS cells inhibits both tumor growth and metastasis in vivo, and that RMS cells are highly sensitive to colony growth inhibition by the pan-JHDM inhibitor JIB-04. Together, our studies reveal an important role for the KDM3A/Ets1/MCAM axis in pediatric sarcomas of distinct cellular and molecular ontogeny, and identify new targetable vulnerabilities in RMS.

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来源期刊
Genes and Cancer
Genes and Cancer Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.90
自引率
0.00%
发文量
6
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