Hairless regulates p53 target genes to exert tumor suppressive functions in glioblastoma

Lemlem Brook, Patricia Palade, Anas Maatough, G Kerr Whitfield, Lis San Emeterio, David Hsieh, Jui-Cheng Hsieh

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor and is associated with a poor prognosis, with most patients living less than a year after diagnosis. Given that GBM nearly always recurs after conventional treatments, there is an urgent need to identify novel molecular targets. Hairless (HR) is a nuclear factor enriched in the skin and has been previously implicated in hair cycling. HR is also highly expressed in the brain, but its significance is unknown. We found that human hairless gene (HR) expression is significantly decreased in all GBM subtypes compared with normal brain tissue and is predictive of prognosis, which suggests that loss of HR expression can contribute to GBM pathogenesis. HR was recently discovered to bind to and regulate p53 responsive elements, and thus we hypothesized that HR may have a tumor suppressive function in GBM by modulating p53 target gene expression. We found that HR indeed regulates p53 target genes, including those implicated in cell cycle progression and apoptosis in the GBM-derived U87 cell line, and restoring HR expression triggered G2/M arrest and apoptosis. An analysis of sequenced genomes from patients with GBM revealed 10 HR somatic mutations in patients with glioma, two of which are located in the histone demethylase domain of HR. These two mutations, P996S and K1004N, were reconstructed and found to have impaired p53 transactivating properties. Collectively, the results of our study suggest that HR has tumor suppressive functions in GBM, which may be clinically relevant and a potential avenue for therapeutic intervention.

Original languageEnglish (US)
JournalJournal of Cellular Biochemistry
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

p53 Genes
Glioblastoma
Tumors
Brain
Genes
Gene expression
Histone Demethylases
Cells
Apoptosis
Neoplasms
Skin
Tissue
Gene Expression
Mutation
Brain Neoplasms
Glioma
Hair
Cell Cycle
Genome
Cell Line

Keywords

  • apoptosis
  • cell cycle arrest
  • hairless (HR)
  • p53 responsive element (p53RE)
  • viability

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hairless regulates p53 target genes to exert tumor suppressive functions in glioblastoma. / Brook, Lemlem; Palade, Patricia; Maatough, Anas; Whitfield, G Kerr; Emeterio, Lis San; Hsieh, David; Hsieh, Jui-Cheng.

In: Journal of Cellular Biochemistry, 01.01.2018.

Research output: Contribution to journalArticle

@article{18583e09c84b49988aa1eeda51c3a214,
title = "Hairless regulates p53 target genes to exert tumor suppressive functions in glioblastoma",
abstract = "Glioblastoma (GBM) is the most common malignant brain tumor and is associated with a poor prognosis, with most patients living less than a year after diagnosis. Given that GBM nearly always recurs after conventional treatments, there is an urgent need to identify novel molecular targets. Hairless (HR) is a nuclear factor enriched in the skin and has been previously implicated in hair cycling. HR is also highly expressed in the brain, but its significance is unknown. We found that human hairless gene (HR) expression is significantly decreased in all GBM subtypes compared with normal brain tissue and is predictive of prognosis, which suggests that loss of HR expression can contribute to GBM pathogenesis. HR was recently discovered to bind to and regulate p53 responsive elements, and thus we hypothesized that HR may have a tumor suppressive function in GBM by modulating p53 target gene expression. We found that HR indeed regulates p53 target genes, including those implicated in cell cycle progression and apoptosis in the GBM-derived U87 cell line, and restoring HR expression triggered G2/M arrest and apoptosis. An analysis of sequenced genomes from patients with GBM revealed 10 HR somatic mutations in patients with glioma, two of which are located in the histone demethylase domain of HR. These two mutations, P996S and K1004N, were reconstructed and found to have impaired p53 transactivating properties. Collectively, the results of our study suggest that HR has tumor suppressive functions in GBM, which may be clinically relevant and a potential avenue for therapeutic intervention.",
keywords = "apoptosis, cell cycle arrest, hairless (HR), p53 responsive element (p53RE), viability",
author = "Lemlem Brook and Patricia Palade and Anas Maatough and Whitfield, {G Kerr} and Emeterio, {Lis San} and David Hsieh and Jui-Cheng Hsieh",
year = "2018",
month = "1",
day = "1",
doi = "10.1002/jcb.27408",
language = "English (US)",
journal = "Journal of Cellular Biochemistry",
issn = "0730-2312",
publisher = "Wiley-Liss Inc.",

}

TY - JOUR

T1 - Hairless regulates p53 target genes to exert tumor suppressive functions in glioblastoma

AU - Brook, Lemlem

AU - Palade, Patricia

AU - Maatough, Anas

AU - Whitfield, G Kerr

AU - Emeterio, Lis San

AU - Hsieh, David

AU - Hsieh, Jui-Cheng

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Glioblastoma (GBM) is the most common malignant brain tumor and is associated with a poor prognosis, with most patients living less than a year after diagnosis. Given that GBM nearly always recurs after conventional treatments, there is an urgent need to identify novel molecular targets. Hairless (HR) is a nuclear factor enriched in the skin and has been previously implicated in hair cycling. HR is also highly expressed in the brain, but its significance is unknown. We found that human hairless gene (HR) expression is significantly decreased in all GBM subtypes compared with normal brain tissue and is predictive of prognosis, which suggests that loss of HR expression can contribute to GBM pathogenesis. HR was recently discovered to bind to and regulate p53 responsive elements, and thus we hypothesized that HR may have a tumor suppressive function in GBM by modulating p53 target gene expression. We found that HR indeed regulates p53 target genes, including those implicated in cell cycle progression and apoptosis in the GBM-derived U87 cell line, and restoring HR expression triggered G2/M arrest and apoptosis. An analysis of sequenced genomes from patients with GBM revealed 10 HR somatic mutations in patients with glioma, two of which are located in the histone demethylase domain of HR. These two mutations, P996S and K1004N, were reconstructed and found to have impaired p53 transactivating properties. Collectively, the results of our study suggest that HR has tumor suppressive functions in GBM, which may be clinically relevant and a potential avenue for therapeutic intervention.

AB - Glioblastoma (GBM) is the most common malignant brain tumor and is associated with a poor prognosis, with most patients living less than a year after diagnosis. Given that GBM nearly always recurs after conventional treatments, there is an urgent need to identify novel molecular targets. Hairless (HR) is a nuclear factor enriched in the skin and has been previously implicated in hair cycling. HR is also highly expressed in the brain, but its significance is unknown. We found that human hairless gene (HR) expression is significantly decreased in all GBM subtypes compared with normal brain tissue and is predictive of prognosis, which suggests that loss of HR expression can contribute to GBM pathogenesis. HR was recently discovered to bind to and regulate p53 responsive elements, and thus we hypothesized that HR may have a tumor suppressive function in GBM by modulating p53 target gene expression. We found that HR indeed regulates p53 target genes, including those implicated in cell cycle progression and apoptosis in the GBM-derived U87 cell line, and restoring HR expression triggered G2/M arrest and apoptosis. An analysis of sequenced genomes from patients with GBM revealed 10 HR somatic mutations in patients with glioma, two of which are located in the histone demethylase domain of HR. These two mutations, P996S and K1004N, were reconstructed and found to have impaired p53 transactivating properties. Collectively, the results of our study suggest that HR has tumor suppressive functions in GBM, which may be clinically relevant and a potential avenue for therapeutic intervention.

KW - apoptosis

KW - cell cycle arrest

KW - hairless (HR)

KW - p53 responsive element (p53RE)

KW - viability

UR - http://www.scopus.com/inward/record.url?scp=85052934011&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052934011&partnerID=8YFLogxK

U2 - 10.1002/jcb.27408

DO - 10.1002/jcb.27408

M3 - Article

C2 - 30191601

AN - SCOPUS:85052934011

JO - Journal of Cellular Biochemistry

JF - Journal of Cellular Biochemistry

SN - 0730-2312

ER -