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首页> 外文期刊>Molecular and Cellular Biology >High-Mobility Group A2 Protein Modulates hTERT Transcription To Promote Tumorigenesis
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High-Mobility Group A2 Protein Modulates hTERT Transcription To Promote Tumorigenesis

机译：高流动性A2组蛋白调节hTERT转录，促进肿瘤发生。

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The high-mobility group A2 gene (HMGA2) is one of the most frequently amplified genes in human cancers. However, functions of HMGA2 in tumorigenesis are not fully understood due to limited knowledge of its targets in tumor cells. Our study reveals a novel link between HMGA2 and the regulation of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, which offers critical insight into how HMGA2 contributes to tumorigenesis. The expression of HMGA2 modulates the expression of hTERT, resulting in cells with enhanced telomerase activities and increased telomere length. Treatment with suberoylanilide hydroxamide (SAHA), a histone deacetylase (HDAC) inhibitor, causes dose-dependent hTERT reporter activation, mimicking HMGA2 overexpression. By interacting with Sp1, HMGA2 interferes with the recruitment of HDAC2 to the hTERT proximal promoter, enhancing localized histone H3-K9 acetylation and thereby stimulating hTERT expression and telomerase activity. Moreover, HMGA2 knockdown by short hairpin HMGA2 in HepG2 cells leads to progressive telomere shortening and a concurrent decrease of steady-state hTERT mRNA levels, attenuating their ability to form colonies in soft agar. Importantly, HMGA2 partially replaces the function of hTERT during the tumorigenic transformation of normal human fibroblasts. These findings are potentially clinically relevant, because HMGA2 expression is reported to be upregulated in a number of human cancers as telomere maintenance is essential for tumorigenesis.
机译：高迁移率的A2类基因（ HMGA2 ）是人类癌症中扩增最频繁的基因之一。然而，由于对肿瘤细胞中的靶标的了解有限，因此尚未完全了解HMGA2在肿瘤发生中的功能。我们的研究揭示了HMGA2与人类端粒酶逆转录酶（hTERT）（端粒酶的催化亚基）的调控之间的新颖联系，这为HMGA2如何促进肿瘤发生提供了重要的见识。 HMGA2的表达调节 hTERT 的表达，从而导致细胞具有增强的端粒酶活性和端粒长度。组蛋白脱乙酰基酶（HDAC）抑制剂Suberoylylanilide Hydroxamide（SAHA）的治疗引起剂量依赖性 hTERT 报告基因激活，模仿HMGA2过表达。通过与Sp1相互作用，HMGA2干扰HDAC2向 hTERT 近端启动子募集，增强局部组蛋白H3-K9乙酰化，从而刺激 hTERT 表达和端粒酶活性。此外，HepG2细胞中由短发夹HMGA2引起的HMGA2敲低导致端粒的进行性缩短和稳态 hTERT mRNA水平的同时下降，从而削弱了它们在软琼脂中形成菌落的能力。重要的是，在正常人成纤维细胞的致瘤转化过程中，HMGA2部分替代了hTERT的功能。这些发现可能与临床相关，因为据报道在许多人类癌症中HMGA2表达上调，因为端粒的维持对于肿瘤的发生至关重要。

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