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.
authors.affiliation: Department of Molecular Pharmacology, City of Hope Beckman Research Institute, Duarte, CA 91010-3000, USA.
authors.forename: Angela Ying-Jian
authors.initials: AY
authors.lastname: Li
authors.forename: Her Helen
authors.initials: HH
authors.lastname: Lin
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Kuo
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.forename: Clay Chia Chun
authors.initials: CC
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: David Kong
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000107:Acetylation; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D056945:Hep G2 Cells; D056464:Histone Deacetylase 2; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D025743:HMGA2 Protein; D019098:Telomerase; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2