Karyotypically abnormal human ESCs are sensitive to HDAC inhibitors and show altered regulation of genes linked to cancers and neurological diseases.
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.
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.
Riikka J
RJ
Lund
Maheswara Reddy
MR
Emani
Ivana
I
Barbaric
Virpi
V
Kivinen
Mark
M
Jones
Duncan
D
Baker
Paul
P
Gokhale
Matti
M
Nykter
Riitta
R
Lahesmaa
Peter W
PW
Andrews
D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002869:Chromosome Aberrations; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D042822:Genomic Instability; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D026502:LDL-Receptor Related Proteins; D034741:RNA, Small Interfering; C506895:SPP1 protein, human; D025521:Tumor Suppressor Proteins; C098773:low density lipoprotein receptor-related protein 8; D053495:Osteopontin; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2