ALT cancer cells are specifically sensitive to lysine acetyl transferase inhibition
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Dalal Bakhos-Douaihy1,2,3,4, Chantal Desmaze1,2,3,4, Maya Jeitany1,2,3,4, Laurent R. Gauthier1,2,3,4, Denis Biard5, Marie-Pierre Junier6, Hervé Chneiweiss6 and François D. Boussin1,2,3,4
1Laboratoire de Radiopathologie, CEA, Institut de Radiobiologie Cellulaire et Moléculaire, Fontenay-aux-Roses, France
2INSERM U1276, Fontenay-aux-Roses, France
3Université Paris-Diderot, U1276, Fontenay-aux-Roses, France
4Université Paris-Sud, U1276, Fontenay-aux-Roses, France
5CEA, Institut de Biologie François Jacob, SEPIA, Team Cellular Engineering and Human Syndromes, Université Paris-Saclay, F-92265 Fontenay-aux-Roses, France
6Neuroscience Paris Seine-IBPS, CNRS UMR8246, Inserm U1130, Sorbonne Université, Paris, France
François D. Boussin, email: [email protected]
Keywords: alternative mechanism of telomere maintenance; PCAF; GCN5; ionizing radiation
Received: February 28, 2018 Accepted: December 20, 2018 Published: January 22, 2019
Some cancer cells elongate their telomeres through the ALT (alternative lengthening of telomeres) pathway, which is based on homologous recombination for the addition of telomere repeats without telomerase activity. General control non-derepressible 5 (GCN5) and P300/CBP-associated factor (PCAF), two homologous lysine acetyltransferases, exert opposite effects on the ALT pathway, inhibiting or favoring it respectively. Here we show that ALT cells are particularly sensitive to the inhibition of acetyltransferases activities using Anacardic Acid (AA). AA treatment recapitulates the effect of PCAF knockdown on several ALT features, suggesting that AA decreased the ALT mechanism through the inhibition of lysine transferase activity of PCAF, but not that of GCN5. Furthermore, AA specifically sensitizes human ALT cells to radiation as compared to telomerase-positive cells suggesting that the inhibition of lysine acetyltransferases activity may be used to increase the radiotherapy efficiency against ALT cancers.
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