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

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2605-2617
Number of pages13
JournalMolecular and Cellular Biology
Volume31
Issue number13
DOIs
Publication statusPublished - Jul 1 2011
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Li, A. Y. J., Lin, H. H., Kuo, C. Y., Shih, H. M., Wang, C. C. C., Yen, Y., & Ann, D. K. (2011). High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis. Molecular and Cellular Biology, 31(13), 2605-2617. https://doi.org/10.1128/MCB.05447-11