Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR

Ligand-dependent corepressor LCoR was identified as a protein that interacts with the estrogen receptor α (ERα) ligand binding domain in a hormone-dependent manner. LCoR also interacts directly with histone deacetylase 3 (HDAC3) and HDAC6. Notably, HDAC6 has emerged as a marker of breast cancer prognosis. However, although HDAC3 is nuclear, HDAC6 is cytoplasmic in many cells. We found that HDAC6 is partially nuclear in estrogen-responsive MCF7 cells, colocalizes with LCoR, represses transactivation of estrogen-inducible reporter genes, and augments corepression by LCoR. In contrast, no repression was observed upon HDAC6 expression in COS7 cells, where it is exclusively cytoplasmic. LCoR binds to HDAC6 in vitro via a central domain, and repression by LCoR mutants lacking this domain was attenuated. Kinetic chromatin immunoprecipitation assays revealed hormone-dependent recruitment of LCoR to promoters of ERα-induced target genes in synchrony with ERα. HDAC6 was also recruited to these promoters, and repeat chromatin immunoprecipitation experiments confirmed the corecruitment of LCoR with ERα and with HDAC6. Remarkably, however, although we find evidence for corecruitment of LCoR and ERα on genes repressed by the receptor, LCoR and HDAC6 failed to coimmunoprecipitate, suggesting that they are part of distinct complexes on these genes. Although small interfering RNA-mediated knockdown of LCoR or HDAC6 augmented expression of an estrogen-sensitive reporter gene in MCF7 cells, unexpectedly their ablation led to reduced expression of some endogenous estrogen target genes. Taken together, these data establish that HDAC6 can function as a cofactor of LCoR but suggest that they may act in enhance expressing some target genes. Ligand-dependent corepressor LCoR was identified as a protein that interacts with the estrogen receptor α (ERα) ligand binding domain in a hormone-dependent manner. LCoR also interacts directly with histone deacetylase 3 (HDAC3) and HDAC6. Notably, HDAC6 has emerged as a marker of breast cancer prognosis. However, although HDAC3 is nuclear, HDAC6 is cytoplasmic in many cells. We found that HDAC6 is partially nuclear in estrogen-responsive MCF7 cells, colocalizes with LCoR, represses transactivation of estrogen-inducible reporter genes, and augments corepression by LCoR. In contrast, no repression was observed upon HDAC6 expression in COS7 cells, where it is exclusively cytoplasmic. LCoR binds to HDAC6 in vitro via a central domain, and repression by LCoR mutants lacking this domain was attenuated. Kinetic chromatin immunoprecipitation assays revealed hormone-dependent recruitment of LCoR to promoters of ERα-induced target genes in synchrony with ERα. HDAC6 was also recruited to these promoters, and repeat chromatin immunoprecipitation experiments confirmed the corecruitment of LCoR with ERα and with HDAC6. Remarkably, however, although we find evidence for corecruitment of LCoR and ERα on genes repressed by the receptor, LCoR and HDAC6 failed to coimmunoprecipitate, suggesting that they are part of distinct complexes on these genes. Although small interfering RNA-mediated knockdown of LCoR or HDAC6 augmented expression of an estrogen-sensitive reporter gene in MCF7 cells, unexpectedly their ablation led to reduced expression of some endogenous estrogen target genes. Taken together, these data establish that HDAC6 can function as a cofactor of LCoR but suggest that they may act in enhance expressing some target genes. Nuclear receptors are ligand-regulated transcription factors whose activities are controlled by a variety of lipophilic extracellular signals, including steroid and thyroid hormones, metabolites of vitamins A (retinoids) and D (1Chawla A. Repa J.J. Evans R.M. Mangelsdorf D.J. Science. 2001; 294: 1866-1870Crossref PubMed Scopus (1671) Google Scholar, 2McKenna N.J. O'Malley B.W. Cell. 2002; 108: 465-474Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar). DNA-bound nuclear receptors regulate transcription by recruiting complexes of coregulatory proteins, classified as coactivators or corepressors depending on whether they act to stimulate or repress transcription (2McKenna N.J. O'Malley B.W. Cell. 2002; 108: 465-474Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar, 3Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar, 4Rosenfeld M.G. Glass C.K. J. Biol. Chem. 2001; 276: 36865-36868Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar). Many coactivators interact with receptors through signature LXXLL motifs, known as NR boxes, which are oriented within a hydrophobic pocket of agonist-bound receptor ligand binding domains (5Renaud J.P. Moras D. Cell. Mol. Life Sci. 2000; 57: 1748-1769Crossref PubMed Scopus (206) Google Scholar). Several coactivators or their associated cofactors possess histone acetyltransferase activity, which essentially caps positively charged lysine residues and their with chromatin and of the to receptor corepressors receptor protein receptor by estrogen in breast cancer binding protein protein for and interfering receptor protein receptor protein receptor by estrogen in breast cancer binding protein protein for and interfering receptor protein and as factors that with but thyroid and receptors Evans R.M. PubMed Scopus Google Scholar, J. A. Glass C.K. Rosenfeld M.G. PubMed Scopus Google Scholar). to receptor ligand binding domains through known as A. Glass C.K. Rosenfeld M.G. Genes Dev. PubMed Scopus Google Scholar, PubMed Scopus Google and complexes in repression and histone (2McKenna N.J. O'Malley B.W. Cell. 2002; 108: 465-474Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar, 3Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar, 4Rosenfeld M.G. Glass C.K. J. Biol. Chem. 2001; 276: 36865-36868Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, J. PubMed Scopus Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R.M. J. Glass C.K. Rosenfeld M.G. PubMed Scopus Google Scholar, D. Evans R.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). binding a in ligand binding domains that to of or corepressors are of complexes distinct of and or histone suggesting that their function on of transcription factors to promoters, and of the identified a LCoR, as an NR protein that with the ligand binding domains of agonist-bound receptors and repressed hormone-dependent transactivation Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). Although LCoR interacts with nuclear receptors in essentially the as it and LCoR interacts directly with HDAC3 and HDAC6 in vitro and with the MCF7 Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). Although LCoR, is a nuclear the of LCoR with HDAC6 is as HDAC6 is cytoplasmic in many Dev. PubMed Scopus Google Scholar). HDAC6 has to function as a deacetylase A. A. A. 2002; PubMed Scopus Google Scholar, A. A. D. J. 2002; PubMed Scopus Google through an controlled by a J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, a of HDAC6 can nuclear in some cells. Notably, experiments in breast cancer revealed that HDAC6 is an estrogen target gene A. PubMed Scopus Google and that HDAC6 protein is in the of breast but is cytoplasmic in PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google Scholar). these found that HDAC6 expression with and to in breast cancer A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google on the we the of HDAC6 in estrogen-responsive MCF7 breast cancer and as an LCoR We find that HDAC6 is partially nuclear in MCF7 and that LCoR and HDAC6 are recruited gene in MCF7 cells. Remarkably, however, although ablation of LCoR or HDAC6 of a reporter the was on endogenous ERα target genes. the that the can act to enhance expression of has the recruitment of corepressor LCoR and associated HDAC6 to genes in MCF7 cells. are in HDAC6 is in and A. D. PubMed Scopus Google and LCoR is as as the of Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). HDAC6 and in the HDAC6 is known for function as a deacetylase A. A. A. 2002; PubMed Scopus Google Scholar). Remarkably, however, HDAC6 are and in D. A. Mol. Cell. Biol. PubMed Scopus Google suggesting that can for some cytoplasmic and nuclear of to has that HDAC6 can or and that function may on that a of HDAC6 was nuclear in breast but cytoplasmic in breast cells, suggesting that nuclear of HDAC6 is on the of of PubMed Scopus Google Scholar). is by the that of a of HDAC6 the to the the and of the A. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). MCF7 ERα and the receptor and are for with a HDAC6 expression is by in MCF7 and breast cancer cells, and of expression with a and to A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google Scholar). In with breast as for a and HDAC6 A. PubMed Scopus Google Scholar). of HDAC6 protein of which was associated with breast cancer in an in vitro A. D. PubMed Scopus Google Scholar). However, that cytoplasmic HDAC6 may enhance and that of the of HDAC6 in may A. PubMed Scopus Google Scholar, J. J. PubMed Scopus Google that LCoR with HDAC6 in vitro and with HDAC6 MCF7 breast cancer Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). However, the cytoplasmic and function of HDAC6 PubMed Scopus Google as as as a marker of breast we in function as an LCoR cofactor We found that a of HDAC6 was nuclear in MCF7 cells. function as an LCoR cofactor was by the that with ERα repressed transactivation in reporter gene assays and that it augmented the of LCoR. was as HDAC6 was cytoplasmic in COS7 and enhance corepression by LCoR. In contrast, which is a and a nuclear repressed hormone-dependent transcription in COS7 cells. expression A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google the that HDAC6 may function with LCoR on some genes as part of a to regulate gene in breast cancer that HDAC6 can function in repression is by that HDAC6 to repression of histone acetyltransferase D. D. A. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). is a of histone acetyltransferase complexes recruited by nuclear including C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar, 4Rosenfeld M.G. Glass C.K. J. Biol. Chem. 2001; 276: 36865-36868Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). A for HDAC6 in repression is also by that it can act as a cofactor of the in J.J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). However, HDAC6 is also associated with the of the whose transcription is by with suggesting that HDAC6 may to of expression Biol. PubMed Scopus Google assays the of cofactors with estrogen target promoters recruitment to a J. Glass PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). We found that recruitment of LCoR to the in this found in MCF7 that recruitment of NR corepressor to the also J. Glass C.K. Rosenfeld M.G. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google the of the LCoR, of represses gene expression in expression PubMed Scopus Google Scholar). to and LCoR, recruitment of corepressors and in the of estrogen was also observed on the J. Glass C.K. Rosenfeld M.G. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. PubMed Scopus Google Scholar). the of with the in the of estrogen has Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). recruitment of and which to act of LCoR or HDAC6 expression in MCF7 augmented and expression of an reporter with the of expression and their as of However, the of ablation of LCoR or HDAC6 on endogenous ERα target genes distinct and of LCoR HDAC6 no on expression of the for We that the of LCoR and associated cofactor function in of estrogen target genes in MCF7 can for by corepressors recruited in the of as or J. M.G. PubMed Scopus Google Scholar). is to that although knockdown of in MCF7 augmented expression of a reporter D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google ablation no on of a of endogenous estrogen target genes in J. J. PubMed Scopus Google the of LCoR or HDAC6 ablation evidence for of these in the of gene LCoR knockdown or reduced expression of and genes by and ablation of LCoR or HDAC6 expression of the and genes. Although these to for LCoR HDAC6 in of gene is with their function as corepressors on the genes of LCoR ablation on endogenous gene expression are also in to in the that LCoR knockdown augmented expression of endogenous target genes A. A. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google is to although the of the of LCoR or HDAC6 ablation on endogenous gene was the are with data in the on in gene of factors associated with gene repression PubMed Scopus Google Scholar). knockdown of in of a of target genes D. Mol. PubMed Scopus Google Scholar). In a of that of to and repression of of genes, evidence for a of in gene and repression PubMed Scopus Google Scholar). of LCoR and HDAC6 to some promoters may for or of of associated with the of gene PubMed Scopus Google evidence that HDAC6 can function as a cofactor of LCoR and that LCoR and HDAC6 are to promoters by Although expression experiments suggest that LCoR and HDAC6 can function as of gene knockdown experiments that the or are for of expression of a of estrogen target genes. Nuclear receptors are ligand-regulated transcription factors whose activities are controlled by a variety of lipophilic extracellular signals, including steroid and thyroid hormones, metabolites of vitamins A (retinoids) and D (1Chawla A. Repa J.J. Evans R.M. Mangelsdorf D.J. Science. 2001; 294: 1866-1870Crossref PubMed Scopus (1671) Google Scholar, 2McKenna N.J. O'Malley B.W. Cell. 2002; 108: 465-474Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar). DNA-bound nuclear receptors regulate transcription by recruiting complexes of coregulatory proteins, classified as coactivators or corepressors depending on whether they act to stimulate or repress transcription (2McKenna N.J. O'Malley B.W. Cell. 2002; 108: 465-474Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar, 3Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar, 4Rosenfeld M.G. Glass C.K. J. Biol. Chem. 2001; 276: 36865-36868Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar). Many coactivators interact with receptors through signature LXXLL motifs, known as NR boxes, which are oriented within a hydrophobic pocket of agonist-bound receptor ligand binding domains (5Renaud J.P. Moras D. Cell. Mol. Life Sci. 2000; 57: 1748-1769Crossref PubMed Scopus (206) Google Scholar). Several coactivators or their associated cofactors possess histone acetyltransferase activity, which essentially caps positively charged lysine residues and their with chromatin and of the to Nuclear receptor corepressors receptor protein receptor by estrogen in breast cancer binding protein protein for and interfering receptor protein receptor protein receptor by estrogen in breast cancer binding protein protein for and interfering receptor protein and as factors that with but thyroid and receptors Evans R.M. PubMed Scopus Google Scholar, J. A. Glass C.K. Rosenfeld M.G. PubMed Scopus Google Scholar). to receptor ligand binding domains through known as A. Glass C.K. Rosenfeld M.G. Genes Dev. PubMed Scopus Google Scholar, PubMed Scopus Google and complexes in repression and histone (2McKenna N.J. O'Malley B.W. Cell. 2002; 108: 465-474Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar, 3Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar, 4Rosenfeld M.G. Glass C.K. J. Biol. Chem. 2001; 276: 36865-36868Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, J. PubMed Scopus Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R.M. J. Glass C.K. Rosenfeld M.G. PubMed Scopus Google Scholar, D. Evans R.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). binding a in ligand binding domains that to of or corepressors are of complexes distinct of and or histone suggesting that their function on of transcription factors to promoters, and of the nuclear receptor corepressor receptor protein chromatin immunoprecipitation estrogen receptor α gene by estrogen in breast cancer protein histone deacetylase binding protein corepressor protein 3 for and receptors A small interfering estrogen nuclear receptor protein nuclear receptor corepressor receptor protein chromatin immunoprecipitation estrogen receptor α gene by estrogen in breast cancer protein histone deacetylase binding protein corepressor protein 3 for and receptors A small interfering estrogen nuclear receptor protein We identified a LCoR, as an NR protein that with the ligand binding domains of agonist-bound receptors and repressed hormone-dependent transactivation Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). Although LCoR interacts with nuclear receptors in essentially the as it and LCoR interacts directly with HDAC3 and HDAC6 in vitro and with the MCF7 Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). Although LCoR, is a nuclear the of LCoR with HDAC6 is as HDAC6 is cytoplasmic in many Dev. PubMed Scopus Google Scholar). HDAC6 has to function as a deacetylase A. A. A. 2002; PubMed Scopus Google Scholar, A. A. D. J. 2002; PubMed Scopus Google through an controlled by a J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, a of HDAC6 can nuclear in some cells. Notably, experiments in breast cancer revealed that HDAC6 is an estrogen target gene A. PubMed Scopus Google and that HDAC6 protein is in the of breast but is cytoplasmic in PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google Scholar). these found that HDAC6 expression with and to in breast cancer A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google Scholar). on the we the of HDAC6 in estrogen-responsive MCF7 breast cancer and as an LCoR We find that HDAC6 is partially nuclear in MCF7 and that LCoR and HDAC6 are recruited gene in MCF7 cells. Remarkably, however, although ablation of LCoR or HDAC6 of a reporter the was on endogenous ERα target genes. the that the can act to enhance expression of genes. has the recruitment of corepressor LCoR and associated HDAC6 to genes in MCF7 cells. are in HDAC6 is in and A. D. PubMed Scopus Google and LCoR is as as the of Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). HDAC6 and in the HDAC6 is known for function as a deacetylase A. A. A. 2002; PubMed Scopus Google Scholar). Remarkably, however, HDAC6 are and in D. A. Mol. Cell. Biol. PubMed Scopus Google suggesting that can for some cytoplasmic and nuclear of to has that HDAC6 can or and that function may on that a of HDAC6 was nuclear in breast but cytoplasmic in breast cells, suggesting that nuclear of HDAC6 is on the of of PubMed Scopus Google Scholar). is by the that of a of HDAC6 the to the the and of the A. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). MCF7 ERα and the receptor and are for with a HDAC6 expression is by in MCF7 and breast cancer cells, and of expression with a and to A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google Scholar). In with breast as for a and HDAC6 A. PubMed Scopus Google Scholar). of HDAC6 protein of which was associated with breast cancer in an in vitro A. D. PubMed Scopus Google Scholar). However, that cytoplasmic HDAC6 may enhance and that of the of HDAC6 in may A. PubMed Scopus Google Scholar, J. J. PubMed Scopus Google that LCoR with HDAC6 in vitro and with HDAC6 MCF7 breast cancer Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). However, the cytoplasmic and function of HDAC6 PubMed Scopus Google as as as a marker of breast we in function as an LCoR cofactor We found that a of HDAC6 was nuclear in MCF7 cells. function as an LCoR cofactor was by the that with ERα repressed transactivation in reporter gene assays and that it augmented the of LCoR. was as HDAC6 was cytoplasmic in COS7 and enhance corepression by LCoR. In contrast, which is a and a nuclear repressed hormone-dependent transcription in COS7 cells. expression A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google the that HDAC6 may function with LCoR on some genes as part of a to regulate gene in breast cancer that HDAC6 can function in repression is by that HDAC6 to repression of histone acetyltransferase D. D. A. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). is a of histone acetyltransferase complexes recruited by nuclear including C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar, 4Rosenfeld M.G. Glass C.K. J. Biol. Chem. 2001; 276: 36865-36868Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). A for HDAC6 in repression is also by that it can act as a cofactor of the in J.J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). However, HDAC6 is also associated with the of the whose transcription is by with suggesting that HDAC6 may to of expression Biol. PubMed Scopus Google assays the of cofactors with estrogen target promoters recruitment to a J. Glass PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). We found that recruitment of LCoR to the in this found in MCF7 that recruitment of NR corepressor to the also J. Glass C.K. Rosenfeld M.G. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google the of the LCoR, of represses gene expression in expression PubMed Scopus Google Scholar). to and LCoR, recruitment of corepressors and in the of estrogen was also observed on the J. Glass C.K. Rosenfeld M.G. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. PubMed Scopus Google Scholar). the of with the in the of estrogen has Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). recruitment of and which to act of LCoR or HDAC6 expression in MCF7 augmented and expression of an reporter with the of expression and their as of However, the of ablation of LCoR or HDAC6 on endogenous ERα target genes distinct and of LCoR HDAC6 no on expression of the for We that the of LCoR and associated cofactor function in of estrogen target genes in MCF7 can for by corepressors recruited in the of as or J. M.G. PubMed Scopus Google Scholar). is to that although knockdown of in MCF7 augmented expression of a reporter D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google ablation no on of a of endogenous estrogen target genes in J. J. PubMed Scopus Google the of LCoR or HDAC6 ablation evidence for of these in the of gene LCoR knockdown or reduced expression of and genes by and ablation of LCoR or HDAC6 expression of the and genes. Although these to for LCoR HDAC6 in of gene is with their function as corepressors on the genes of LCoR ablation on endogenous gene expression are also in to in the that LCoR knockdown augmented expression of endogenous target genes A. A. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google is to although the of the of LCoR or HDAC6 ablation on endogenous gene was the are with data in the on in gene of factors associated with gene repression PubMed Scopus Google Scholar). knockdown of in of a of target genes D. Mol. PubMed Scopus Google Scholar). In a of that of to and repression of of genes, evidence for a of in gene and repression PubMed Scopus Google Scholar). of LCoR and HDAC6 to some promoters may for or of of associated with the of gene PubMed Scopus Google evidence that HDAC6 can function as a cofactor of LCoR and that LCoR and HDAC6 are to promoters by Although expression experiments suggest that LCoR and HDAC6 can function as of gene knockdown experiments that the or are for of expression of a of estrogen target genes. has the recruitment of corepressor LCoR and associated HDAC6 to genes in MCF7 cells. are in HDAC6 is in and A. D. PubMed Scopus Google and LCoR is as as the of Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). HDAC6 and in the HDAC6 is known for function as a deacetylase A. A. A. 2002; PubMed Scopus Google Scholar). Remarkably, however, HDAC6 are and in D. A. Mol. Cell. Biol. PubMed Scopus Google suggesting that can for some cytoplasmic and nuclear of HDAC6. to has that HDAC6 can or and that function may on that a of HDAC6 was nuclear in breast but cytoplasmic in breast cells, suggesting that nuclear of HDAC6 is on the of of PubMed Scopus Google Scholar). is by the that of a of HDAC6 the to the the and of the A. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). MCF7 ERα and the receptor and are for with a HDAC6 expression is by in MCF7 and breast cancer cells, and of expression with a and to A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google Scholar). In with breast as for a and HDAC6 A. PubMed Scopus Google Scholar). of HDAC6 protein of which was associated with breast cancer in an in vitro A. D. PubMed Scopus Google Scholar). However, that cytoplasmic HDAC6 may enhance and that of the of HDAC6 in may A. PubMed Scopus Google Scholar, J. J. PubMed Scopus Google Scholar). that LCoR with HDAC6 in vitro and with HDAC6 MCF7 breast cancer Mol. Cell. Full Text Full Text PDF PubMed Scopus (206) Google Scholar). However, the cytoplasmic and function of HDAC6 PubMed Scopus Google as as as a marker of breast we in function as an LCoR cofactor We found that a of HDAC6 was nuclear in MCF7 cells. function as an LCoR cofactor was by the that with ERα repressed transactivation in reporter gene assays and that it augmented the of LCoR. was as HDAC6 was cytoplasmic in COS7 and enhance corepression by LCoR. In contrast, which is a and a nuclear repressed hormone-dependent transcription in COS7 cells. expression A. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, A. Sci. PubMed Scopus Google the that HDAC6 may function with LCoR on some genes as part of a to regulate gene in breast cancer cells. that HDAC6 can function in repression is by that HDAC6 to repression of histone acetyltransferase D. D. A. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). is a of histone acetyltransferase complexes recruited by nuclear including C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar, 4Rosenfeld M.G. Glass C.K. J. Biol. Chem. 2001; 276: 36865-36868Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). A for HDAC6 in repression is also by that it can act as a cofactor of the in J.J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). However, HDAC6 is also associated with the of the whose transcription is by with suggesting that HDAC6 may to of expression Biol. PubMed Scopus Google Scholar). Kinetic assays the of cofactors with estrogen target promoters recruitment to a J. Glass PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). We found that recruitment of LCoR to the in this found in MCF7 that recruitment of NR corepressor to the also J. Glass C.K. Rosenfeld M.G. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google the of the LCoR, of represses gene expression in expression PubMed Scopus Google Scholar). to and LCoR, recruitment of corepressors and in the of estrogen was also observed on the J. Glass C.K. Rosenfeld M.G. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. PubMed Scopus Google Scholar). the of with the in the of estrogen has Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). recruitment of and which to act of LCoR or HDAC6 expression in MCF7 augmented and expression of an reporter with the of expression and their as of However, the of ablation of LCoR or HDAC6 on endogenous ERα target genes distinct and of LCoR HDAC6 no on expression of the for We that the of LCoR and associated cofactor function in of estrogen target genes in MCF7 can for by corepressors recruited in the of as or J. M.G. PubMed Scopus Google Scholar). is to that although knockdown of in MCF7 augmented expression of a reporter D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google ablation no on of a of endogenous estrogen target genes in J. J. PubMed Scopus Google Scholar). the of LCoR or HDAC6 ablation evidence for of these in the of gene LCoR knockdown or reduced expression of and genes by and ablation of LCoR or HDAC6 expression of the and genes. Although these to for LCoR HDAC6 in of gene is with their function as corepressors on the genes of LCoR ablation on endogenous gene expression are also in to in the that LCoR knockdown augmented expression of endogenous target genes A. A. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is to although the of the of LCoR or HDAC6 ablation on endogenous gene was the are with data in the on in gene of factors associated with gene repression PubMed Scopus Google Scholar). knockdown of in of a of target genes D. Mol. PubMed Scopus Google Scholar). In a of that of to and repression of of genes, evidence for a of in gene and repression PubMed Scopus Google Scholar). of LCoR and HDAC6 to some promoters may for or of of associated with the of gene PubMed Scopus Google Scholar). In evidence that HDAC6 can function as a cofactor of LCoR and that LCoR and HDAC6 are to promoters by Although expression experiments suggest that LCoR and HDAC6 can function as of gene knockdown experiments that the or are for of expression of a of estrogen target genes. We are to for and to for with A to for the of

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