The secrets of the X chromosome have now been revealed with the publication of its sequence (Ross, M. T. et al. Nature 434, 325–337 (2005)), and information hidden within this data could help promising cancer drugs that target epigenetic mechanisms.

The X chromosome is unique in that the expression of most of the genes on one of the two X chromosomes in female mammals are inactivated. Inactivating one X ensures that females by and large have the same dosage of gene products as males, who only have one X chromosome.

This X-chromosome inactivation process is driven by epigenetic regulation — the heritable silencing of genes without changes to their coding sequences. The Nature paper reveals that mobile genetic sequence elements called L1 repeats could serve as booster signals for this process.

Cancer researchers have long been interested in the roles that epigenetic mechanisms have in the activation and silencing of genes in tumours. Inhibitors are being developed against DNA methylation and the protein histone deacetylase (HDAC), both of which reactivate genes that have been epigenetically silenced. One DNA methylation inhibitor, 5-azacytidine (Vidaza; Pharmion), was approved for myelodysplastic syndrome by the FDA in May 2004.

Little is known about the long-term effects of these inhibitors, and no study has looked specifically at whether genes on the inactive X chromosome are reactivated. Many research groups, wary of the effects of reactivating previously inactive genes, are using microarray studies on cancer cells in culture treated with 5-azacytidine or HDAC inhibitors to see which genes are modulated.

A paper recently published in PNAS shows that different HDAC inhibitors alter transcription of a large and common set of genes that control several molecular pathways that are involved in cell survival and apoptosis (Peart, M. J. et al. PNAS 102, 3697–3702 (2005)).

“Our findings show that HDAC inhibitors are quite selective in the genes whose transcription is altered,” says Paul Marks, President Emeritus and Member at the Memorial Sloan-Kettering Cancer Center, New York, and one of the co-authors of the paper.

Susan Clark is investigating the effects of 5-azacytidine and other DNA-methylation agents. “We were not specifically looking for X-linked genes but we did see X-linked genes as well as genes from the chromosomes that had become increased in expression,” says Clark, Epigenetic Research Group Leader at The Garvan Institute of Medical Research, Darlinghurst, Australia.

Whether these are from the inactive X chromosome is difficult to tell. “Without polymorphic markers it is impossible to interpret whether the X-linked genes that are activated by treatment are from the inactive X or if the increase in expression is from the active X,” says Clark.

But with the sequence of the X chromosome in hand the identification of polymorphic markers could now be possible, and other aspects of epigenetic mechanisms in cancer might be revealed. “The X chromosome provides a model system for understanding epigenetic regulation and misregulation,” says Edith Heard, at the Mammalian Developmental Epigenetics Group, Curie Institute Paris. “The behaviour of the inactive X following various treatments will be critical.”