PMID- 35406744
OWN - NLM
STAT- MEDLINE
DCOM- 20220413
LR  - 20220531
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 7
DP  - 2022 Mar 31
TI  - The Sin3A/MAD1 Complex, through Its PAH2 Domain, Acts as a Second Repressor of 
      Retinoic Acid Receptor Beta Expression in Breast Cancer Cells.
LID - 10.3390/cells11071179 [doi]
LID - 1179
AB  - Retinoids are essential in balancing proliferation, differentiation and 
      apoptosis, and they exert their effects through retinoic acid receptors (RARs) 
      and retinoid X receptors (RXRs). RARbeta is a tumor-suppressor gene silenced by 
      epigenetic mechanisms such as DNA methylation in breast, cervical and non-small 
      cell lung cancers. An increased expression of RARbeta has been associated with 
      improved breast cancer-specific survival. The PAH2 domain of the scaffold protein 
      SIN3A interacts with the specific Sin3 Interaction Domain (SID) of several 
      transcription factors, such as MAD1, bringing chromatin-modifying proteins such 
      as histone deacetylases, and it targets chromatin for specific modifications. 
      Previously, we have established that blocking the PAH2-mediated Sin3A interaction 
      with SID-containing proteins using SID peptides or small molecule inhibitors 
      (SMI) increased RARbeta expression and induced retinoic acid metabolism in breast 
      cancer cells, both in in vitro and in vivo models. Here, we report studies 
      designed to understand the mechanistic basis of RARbeta induction and function. 
      Using human breast cancer cells transfected with MAD1 SID or treated with the MAD 
      SID peptide, we observed a dissociation of MAD1, RARalpha and RARbeta from Sin3A in a 
      coimmunoprecipitation assay. This was associated with increased RARalpha and RARbeta 
      expression and function by a luciferase assay, which was enhanced by the addition 
      of AM580, a specific RARalpha agonist; EMSA showed that MAD1 binds to E-Box, similar 
      to MYC, on the RARbeta promoter, which showed a reduced enrichment of Sin3A and 
      HDAC1 by ChIP and was required for the AM580-enhanced RARbeta activation in MAD1/SID 
      cells. These data suggest that the Sin3A/HDAC1/2 complex co-operates with the 
      classical repressors in regulating RARbeta expression. These data suggest that 
      SIN3A/MAD1 acts as a second RARbeta repressor and may be involved in fine-tuning 
      retinoid sensitivity.
FAU - Dahiya, Nisha Rani
AU  - Dahiya NR
AD  - The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 
      10029, USA.
FAU - Leibovitch, Boris A
AU  - Leibovitch BA
AUID- ORCID: 0000-0001-6771-5906
AD  - Department of Pathology, New York University School of Medicine, New York, NY 
      10029, USA.
FAU - Kadamb, Rama
AU  - Kadamb R
AUID- ORCID: 0000-0002-0157-2305
AD  - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, 
      USA.
FAU - Bansal, Nidhi
AU  - Bansal N
AUID- ORCID: 0000-0001-6502-3930
AD  - The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 
      10029, USA.
FAU - Waxman, Samuel
AU  - Waxman S
AD  - The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 
      10029, USA.
LA  - eng
GR  - R01 CA158121/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20220331
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Chromatin)
RN  - 0 (MAD1L1 protein, human)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Repressor Proteins)
RN  - 0 (SIN3A transcription factor)
RN  - 0 (retinoic acid receptor beta)
RN  - EC 3.5.1.98 (Sin3 Histone Deacetylase and Corepressor Complex)
SB  - IM
MH  - *Breast Neoplasms/genetics/metabolism
MH  - *Cell Cycle Proteins/genetics
MH  - Chromatin
MH  - Female
MH  - Humans
MH  - *Receptors, Retinoic Acid/metabolism
MH  - Repressor Proteins/metabolism
MH  - *Sin3 Histone Deacetylase and Corepressor Complex/genetics
PMC - PMC8997856
OTO - NOTNLM
OT  - E-box
OT  - HDAC: histone deacetylases
OT  - MAD1: MAX dimerization protein
OT  - NCoR: nuclear receptor corepressor 1
OT  - PAH: paired amphipathic domains
OT  - RARE: retinoic acid response element
OT  - RARbeta: retinoic acid receptor beta
OT  - Sin3A
OT  - breast cancer
OT  - co-immunoprecipitation
COIS- The authors declare no conflict of interest.
EDAT- 2022/04/13 06:00
MHDA- 2022/04/14 06:00
PMCR- 2022/03/31
CRDT- 2022/04/12 01:05
PHST- 2022/01/05 00:00 [received]
PHST- 2022/03/24 00:00 [revised]
PHST- 2022/03/25 00:00 [accepted]
PHST- 2022/04/12 01:05 [entrez]
PHST- 2022/04/13 06:00 [pubmed]
PHST- 2022/04/14 06:00 [medline]
PHST- 2022/03/31 00:00 [pmc-release]
AID - cells11071179 [pii]
AID - cells-11-01179 [pii]
AID - 10.3390/cells11071179 [doi]
PST - epublish
SO  - Cells. 2022 Mar 31;11(7):1179. doi: 10.3390/cells11071179.