Karyotypically abnormal human ESCs are sensitive to HDAC inhibitors and show altered regulation of genes linked to cancers and neurological diseases

Riikka J Lund; Maheswara Reddy Emani; Ivana Barbaric; Virpi Kivinen; Mark Jones; Duncan Baker; Paul Gokhale; Matti Nykter; Riitta Lahesmaa; Peter W Andrews

doi:10.1016/j.scr.2013.07.002

Karyotypically abnormal human ESCs are sensitive to HDAC inhibitors and show altered regulation of genes linked to cancers and neurological diseases

Stem Cell Res. 2013 Nov;11(3):1022-36. doi: 10.1016/j.scr.2013.07.002. Epub 2013 Jul 18.

Authors

Riikka J Lund¹, Maheswara Reddy Emani, Ivana Barbaric, Virpi Kivinen, Mark Jones, Duncan Baker, Paul Gokhale, Matti Nykter, Riitta Lahesmaa, Peter W Andrews

Affiliation

¹ Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, UK; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku FI-20520, Finland. Electronic address: riikka.lund@btk.fi.

PMID: 23941963
DOI: 10.1016/j.scr.2013.07.002

Abstract

Genomic abnormalities may accumulate in human embryonic stem cells (hESCs) during in vitro maintenance. Characterization of the mechanisms enabling survival and expansion of abnormal hESCs is important due to consequences of genetic changes for the therapeutic utilization of stem cells. Furthermore, these cells provide an excellent model to study transformation in vitro. We report here that the histone deacetylase proteins, HDAC1 and HDAC2, are increased in karyotypically abnormal hESCs when compared to their normal counterparts. Importantly, similar to many cancer cell lines, we found that HDAC inhibitors repress proliferation of the karyotypically abnormal hESCs, whereas normal cells are more resistant to the treatment. The decreased proliferation correlates with downregulation of HDAC1 and HDAC2 proteins, induction of the proliferation inhibitor, cyclin-dependent kinase inhibitor 1A (CDKN1A), and altered regulation of tumor suppressor protein Retinoblastoma 1 (RB1). Through genome-wide transcriptome analysis we have identified genes with altered expression and responsiveness to HDAC inhibition in abnormal cells. Most of these genes are linked to severe developmental and neurological diseases and cancers. Our results highlight the importance of epigenetic mechanisms in the regulation of genomic stability of hESCs, and provide valuable candidates for targeted and selective growth inhibition of karyotypically abnormal cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / drug effects
Cell Line
Cell Proliferation / drug effects
Chromosome Aberrations*
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Down-Regulation / drug effects
Embryonic Stem Cells / cytology
Embryonic Stem Cells / drug effects*
Embryonic Stem Cells / metabolism
Gene Expression Regulation*
Genomic Instability
Histone Deacetylase 1 / antagonists & inhibitors
Histone Deacetylase 1 / genetics
Histone Deacetylase 1 / metabolism
Histone Deacetylase 2 / antagonists & inhibitors
Histone Deacetylase 2 / metabolism
Histone Deacetylase Inhibitors / pharmacology*
Humans
LDL-Receptor Related Proteins / genetics
LDL-Receptor Related Proteins / metabolism
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology
Nervous System Diseases / genetics
Nervous System Diseases / metabolism
Nervous System Diseases / pathology
Osteopontin / genetics
Osteopontin / metabolism
RNA, Small Interfering / metabolism
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

Cyclin-Dependent Kinase Inhibitor p21
Histone Deacetylase Inhibitors
LDL-Receptor Related Proteins
RNA, Small Interfering
SPP1 protein, human
Tumor Suppressor Proteins
low density lipoprotein receptor-related protein 8
Osteopontin
HDAC1 protein, human
HDAC2 protein, human
Histone Deacetylase 1
Histone Deacetylase 2