Cohesin, a multi-subunit protein complex involved in chromosome organisation, 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 alpha (ER) recruitment atSOX4andIL20, 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.
Pharmacology, Toxicology and Pharmaceutical Science
3
4%
Engineering
3
4%
Other
7
9%
Unknown
26
34%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 23 April 2016.
All research outputs
#14,278,325
of 25,377,790 outputs
Outputs from Journal of Biological Chemistry
#72,163
of 85,237 outputs
Outputs of similar age
#146,033
of 316,300 outputs
Outputs of similar age from Journal of Biological Chemistry
#155
of 406 outputs
Altmetric has tracked 25,377,790 research outputs across all sources so far. This one is in the 43rd percentile – i.e., 43% of other outputs scored the same or lower than it.
So far Altmetric has tracked 85,237 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.1. This one is in the 15th percentile – i.e., 15% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 316,300 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 53% of its contemporaries.
We're also able to compare this research output to 406 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 61% of its contemporaries.
