High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis

Angela Ying Jian Li, Her Helen Lin, Ching Ying Kuo, Hsiu Ming Shih, Clay Chia Chun Wang, Yun Yen, David Kong Ann

研究成果: 雜誌貢獻文章同行評審

42 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)2605-2617
頁數13
期刊Molecular and Cellular Biology
31
發行號13
DOIs
出版狀態已發佈 - 七月 2011
對外發佈

ASJC Scopus subject areas

  • 分子生物學
  • 細胞生物學

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