Suppressing Cancer Transcriptional Regulatory Complex Activity May Depend on Inositol Phosphate Signaling

They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation.

Investigators at the University of Leicester (United Kingdom) described the structure of a complex between an HDAC and a corepressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor in the January 9, 2012, online edition of the journal Nature.

The structure revealed two remarkable features. First, the SMRT-DAD underwent a large structural rearrangement on forming the complex. Second, there was an essential inositol tetraphosphate molecule -- d-myo-inositol-(1,4,5,6)-tetrakisphosphate -- acting as an “intermolecular glue” between the two proteins.

Senior author Dr. John Schwabe, professor of biochemistry at the University of Leicester, said, “We have discovered a completely new and unexpected link between inositol phosphate signaling (in this case IP4) and the regulation of histone deacetylase enzymes, and hence transcriptional repression or gene silencing. In simple terms, we have shown that IP4 acts as a natural signaling molecule to regulate histone deacetylase enzymes, which play a key role in regulating gene expression. Apart from the considerable intellectual importance of understanding how transcription is regulated, repression complexes are important therapeutic targets for a number of cancers including several types of leukemia.”

“Our research identifies several new means to potentially target histone deacetylase enzymes therapeutically, either by using drugs to prevent IP4 binding to the enzyme or by interfering with the pathway through which the body makes IP4,” said Dr. Schwabe. “Thus, this work opens up a whole new area of research with potential for new drugs and a new approach to targeting histone deacetylase enzymes.”

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