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

35 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

High Mobility Group Proteins
varespladib methyl
Reverse Transcription
Carcinogenesis
Telomerase
Genes
Telomere
human TERT protein
Neoplastic Cell Transformation
Gene Knockdown Techniques
Telomere Shortening
Gene Expression
Neoplasms
Histone Deacetylase Inhibitors
Hep G2 Cells
Acetylation
Histones
Agar
Fibroblasts

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

High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis. / Li, Angela Ying Jian; Lin, Her Helen; Kuo, Ching Ying; Shih, Hsiu Ming; Wang, Clay Chia Chun; Yen, Yun; Ann, David Kong.

In: Molecular and Cellular Biology, Vol. 31, No. 13, 01.07.2011, p. 2605-2617.

Research output: Contribution to journalArticle

Li, Angela Ying Jian ; Lin, Her Helen ; Kuo, Ching Ying ; Shih, Hsiu Ming ; Wang, Clay Chia Chun ; Yen, Yun ; Ann, David Kong. / High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis. In: Molecular and Cellular Biology. 2011 ; Vol. 31, No. 13. pp. 2605-2617.
@article{d3129adf950f45909b954af9f5971964,
title = "High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis",
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.",
author = "Li, {Angela Ying Jian} and Lin, {Her Helen} and Kuo, {Ching Ying} and Shih, {Hsiu Ming} and Wang, {Clay Chia Chun} and Yun Yen and Ann, {David Kong}",
year = "2011",
month = "7",
day = "1",
doi = "10.1128/MCB.05447-11",
language = "English",
volume = "31",
pages = "2605--2617",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "13",

}

TY - JOUR

T1 - High-mobility group A2 protein modulates hTERT transcription to promote tumorigenesis

AU - Li, Angela Ying Jian

AU - Lin, Her Helen

AU - Kuo, Ching Ying

AU - Shih, Hsiu Ming

AU - Wang, Clay Chia Chun

AU - Yen, Yun

AU - Ann, David Kong

PY - 2011/7/1

Y1 - 2011/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79959419265&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959419265&partnerID=8YFLogxK

U2 - 10.1128/MCB.05447-11

DO - 10.1128/MCB.05447-11

M3 - Article

VL - 31

SP - 2605

EP - 2617

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 13

ER -