Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Biol Chem. 2020 Jun 26;295(26):8834-8845. doi: 10.1074/jbc.RA120.013530. Epub 2020 May 12.
Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with an average life expectancy of ∼6 months from the time of diagnosis. The genetic and epigenetic changes that underlie this malignancy are incompletely understood. We found that ASH1-like histone lysine methyltransferase (ASH1L) is overexpressed in ATC relative to the much less aggressive and more common differentiated thyroid cancer. This increased expression was due at least in part to reduced levels of microRNA-200b-3p (miR-200b-3p), which represses ASH1L expression, in ATC. Genetic knockout of ASH1L protein expression in ATC cell lines decreased cell growth both in culture and in mouse xenografts. RNA-Seq analysis of ASH1L knockout WT ATC cell lines revealed that ASH1L is involved in the regulation of numerous cancer-related genes and gene sets. The pro-oncogenic long noncoding RNA colon cancer-associated transcript 1 (CCAT1) was one of the most highly (approximately 68-fold) down-regulated transcripts in ASH1L knockout cells. Therefore, we investigated CCAT1 as a potential mediator of the growth-inducing activity of ASH1L. Supporting this hypothesis, CCAT1 knockdown in ATC cells decreased their growth rate, and ChIP-Seq data indicated that CCAT1 is likely a direct target of ASH1L's histone methyltransferase activity. These results indicate that ASH1L contributes to the aggressiveness of ATC and suggest that ASH1L, along with its upstream regulator miR-200b-3p and its downstream mediator CCAT1, represents a potential therapeutic target in ATC.
间变性甲状腺癌 (ATC) 是最具侵袭性的人类恶性肿瘤之一，从诊断到死亡的平均预期寿命约为 6 个月。导致这种恶性肿瘤的遗传和表观遗传变化尚未完全了解。我们发现，与侵袭性和常见得多的分化型甲状腺癌相比，ASH1 样组蛋白赖氨酸甲基转移酶 (ASH1L) 在 ATC 中过度表达。这种表达增加至少部分归因于 microRNA-200b-3p (miR-200b-3p) 的水平降低，miR-200b-3p 抑制 ASH1L 的表达。在 ATC 细胞系中敲除 ASH1L 蛋白表达会降低细胞在培养中和小鼠异种移植中的生长。对 ASH1L 敲除的 ATC 细胞系进行 RNA-Seq 分析显示，ASH1L 参与了许多与癌症相关的基因和基因集的调控。致癌性长非编码 RNA 结肠癌相关转录物 1 (CCAT1) 是 ASH1L 敲除细胞中下调最明显的转录物之一（约 68 倍）。因此，我们研究了 CCAT1 作为 ASH1L 诱导生长活性的潜在介质。支持这一假说，在 ATC 细胞中敲低 CCAT1 会降低其生长速度，ChIP-Seq 数据表明 CCAT1 可能是 ASH1L 组蛋白甲基转移酶活性的直接靶标。这些结果表明，ASH1L 有助于 ATC 的侵袭性，并表明 ASH1L 与其上游调节因子 miR-200b-3p 和下游介质 CCAT1 一起，代表 ATC 中的一个潜在治疗靶点。
