Oncotarget

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Carbonic anhydrase IX induction defines a heterogeneous cancer cell response to hypoxia and mediates stem cell-like properties and sensitivity to HDAC inhibition

Ioanna Ledaki, Alan McIntyre, Simon Wigfield, Francesca Buffa, Simon McGowan, Dilair Baban, Ji-liang Li and Adrian L. Harris _

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Oncotarget. 2015; 6:19413-19427. https://doi.org/10.18632/oncotarget.4989

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Abstract

Ioanna Ledaki1,*, Alan McIntyre1,*, Simon Wigfield1, Francesca Buffa1, Simon McGowan1, Dilair Baban2, Ji-liang Li1 and Adrian L. Harris1

1 Molecular Oncology Laboratories, Department of Oncology, University of Oxford, Weatherall Institute of Molecular Medicine, Oxford, UK

2 High Throughput Genomics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

* These authors contributed equally to this work

Correspondence to:

Adrian L. Harris, email:

Keywords: carbonic anhydrase IX; stem cells; hypoxia; EMT; tumour heterogeneity

Received: April 16, 2015 Accepted: July 16, 2015 Published: July 22, 2015

Abstract

Carbonic anhydrase IX (CAIX) is strongly induced by hypoxia and its overexpression is associated with poor therapeutic outcome in cancer. Here, we report that hypoxia promotes tumour heterogeneity through the epigenetic regulation of CAIX. Based on hypoxic CAIX expression we identify and characterize two distinct populations of tumour cells, one that has inducible expression of CAIX and one that does not. The CAIX+ve population is enriched with cells expressing cancer stem cell markers and which have high self-renewal capacity. We show that differential CAIX expression is due to differences in chromatin structure. To further investigate the relationship between chromatin organization and hypoxic induction of CAIX expression we investigated the effect of JQ1 an inhibitor of BET bromodomain proteins and A366 a selective inhibitor of the H3K9 methyltransferase G9a/GLP. We identified that these drugs were able to modulate hypoxic CAIX expression induction. This further highlights the role of epigenetic modification in adaption to hypoxia and also in regulation of heterogeneity of cells within tumours. Interestingly, we identified that the two subpopulations show a differential sensitivity to HDAC inhibitors, NaBu or SAHA, with the CAIX positive showing greater sensitivity to treatment. We propose that drugs modulating chromatin regulation of expression may be used to reduce heterogeneity induced by hypoxia and could in combination have significant clinical consequences.


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