Cohesin, a multi-subunit protein complex involved in chromosome organization, is frequently mutated or aberrantly expressed in cancer. Multiple functions of cohesin, including cell division and gene expression, highlight its potential as a novel therapeutic target. The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes. Following anaphase, ac-SMC3 is deacetylated by HDAC8. Reversal of SMC3 acetylation is imperative for recycling cohesin so that it can be reloaded in interphase for both non-mitotic and mitotic functions. We blocked deacetylation of ac-SMC3 using an HDAC8-specific inhibitor PCI-34051 in MCF7 breast cancer cells, and examined the effects on transcription of cohesin-dependent genes that respond to estrogen. HDAC8 inhibition led to accumulation of ac-SMC3 as expected, but surprisingly, had no influence on the transcription of estrogen-responsive genes that are altered by siRNA targeting of RAD21 or SMC3. Knockdown of RAD21 altered estrogen receptor ␣ (ER) recruitment at SOX4 and IL20, and affected transcription of these genes, while HDAC8 inhibition did not. Rather, inhibition of HDAC8 delayed cell cycle progression, suppressed proliferation and induced apoptosis in a concentration-dependent manner. We conclude that HDAC8 inhibition does not change the estrogen-specific transcriptional role of cohesin in MCF7 cells, but instead, compromises cell cycle progression and cell survival. Our results argue that candidate inhibitors of cohesin function may differ in their effects depending on the cellular genotype and should be thoroughly tested for predicted effects on cohesin's mechanistic roles.The cohesin complex is a chromatin-associated multi-subunit protein comprised of two SMC (structural maintenance of chromosomes, SMC1A and SMC3) 2 and two non-SMC subunits (RAD21, STAG1/2). Cohesin's canonical function establishes cohesion between replicated sister chromatids, thus ensuring their precise segregation at anaphase (1, 2). Research over the last one and a half decades has revealed that cohesin has additional cohesion-independent functions in interphase nuclei, such as chromatin organization and transcription regulation (3, 4).Recently, cancer genome sequencing projects have revealed that genes encoding cohesin subunits are frequently mutated in several different types of cancer, with particularly high frequency in acute myeloid leukemia (AML) (5-9). Recent mouse models indicate that cohesin contributes to leukemia progression likely through controlling transcription and genome organization, rather than through chromosome separation (10 -12). In breast cancer, the cohesin subunit RAD21 is overexpressed and confers poor prognosis (13,14). We previously showed that cohesin mediates transcription of the MYC gene (15-17) and modulates the transcription of estrogen-dependent genes in MCF7 breast cancer cells (18). The emergence of cohesin as an important contributor to cancer has generated interest in the development of therapeutics that compromise ...
