Rabbit Anti-Human HDAC8 monoclonal antibody, clone KK1956

In addition to its role in sister chromatid cohesion, genome stability and integrity, the cohesin complex is involved in gene transcription. Mutations in core cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, cause Cornelia de Lange syndrome (CdLS). Recent evidence reveals that gene expression dysregulation could be the underlying mechanism for CdLS. These findings raise intriguing questions regarding the potential role of cohesin-mediated transcriptional control and pathogenesis. Here, we identified numerous dysregulated genes occupied by cohesin by combining the transcriptome of CdLS cell lines carrying mutations in SMC1A gene and ChIP-Seq data. Genome-wide analyses show that genes changing in expression are enriched for cohesin-binding. In addition, our results indicate that mutant cohesin impairs both RNA polymerase II (Pol II) transcription initiation at promoters and elongation in the gene body. These findings highlight the pivotal role of cohesin in transcriptional regulation and provide an explanation for the typical gene dysregulation observed in CdLS patients.

We previously identified 3-hydroxypyridine-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but devoid of HDAC1 inhibition. To delineate further the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds, 10d and 14e, with potent HDAC6 and HDAC8 activities that are inactive against HDAC1. These new HDACi possess anticancer activities against various cancer cell lines including Jurkat J.gamma 1 for which SAHA and the previously disclosed 3HPT-derived HDACi were inactive.