Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells
Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However, the underlying mechanisms are largely unknown. In this study, we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels of HDAC isozymes in triple-negative breast cancer (TNBC) cells. Small interfering RNA (siRNA)-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, pargyline, and HDAC inhibitor, SAHA (Vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA-induced reexpression of a subset of aberrantly silenced genes, such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1-deficient MDA-MB-231 cells. Furthermore, cotreatment with RGS16 siRNA reversed the downregulation of nuclear factor-kappaB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor.
Pharmacology, Toxicology and Pharmaceutical Science
5
6%
Medicine and Dentistry
3
4%
Other
5
6%
Unknown
16
20%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 7. 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 03 March 2026.
All research outputs
#7,319,939
of 34,089,221 outputs
Outputs from Carcinogenesis
#1,321
of 5,927 outputs
Outputs of similar age
#66,160
of 341,879 outputs
Outputs of similar age from Carcinogenesis
#18
of 49 outputs
Altmetric has tracked 34,089,221 research outputs across all sources so far. Compared to these this one has done well and is in the 78th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 5,927 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 7.6. This one has done well, scoring higher than 77% of its peers.
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 341,879 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 80% of its contemporaries.
We're also able to compare this research output to 49 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 63% of its contemporaries.
