ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERα, is required for coregulator occupancy and chromatin modification

AAA+ proteins play crucial roles in diverse biological processes via their ATPase-driven remodeling of macromolecular complexes. Here we report our identification of an evolutionarily conserved AAA+ protein, ANCCA/pro2000, endowed with a bromodomain that is strongly induced by estrogen in human breast cancer cells and is a direct target of protooncogene ACTR/AIB1/SRC-3. We found that ANCCA associates directly with estrogen-bound estrogen receptor (ER) α and ACTR. It is selectively recruited, upon estrogen stimulation, to a subset of ERα target genes including cyclin D1, c-myc, and E2F1 and is required for their estrogen-induced expression as well as breast cancer cell proliferation. Further studies indicate that ANCCA binds and hydrolyzes ATP and is critical for recruitment of coregulator CBP and histone hyperacetylation at the ER target chromatin. Moreover, mutations at the ATP binding motifs rendered ANCCA defective as a coactivator in mediating estrogen induction of gene expression. Together, our findings reveal an unexpected layer of regulatory mechanism in hormone signaling mediated by ANCCA and suggest that hormone-induced assembly of transcriptional coregulator complexes at chromatin is a process facilitated by AAA+ ATPase proteins.

[1]  A. Steven,et al.  Structural and enzymatic properties of the AAA protein Drg1p from Saccharomyces cerevisiae. Decoupling of intracellular function from ATPase activity and hexamerization. , 2002, The Journal of biological chemistry.

[2]  Sandya Liyanarachchi,et al.  Combinatorial analysis of transcription factor partners reveals recruitment of c-MYC to estrogen receptor-alpha responsive promoters. , 2006, Molecular cell.

[3]  V. Craig Jordan,et al.  International Union of Pharmacology. LXIV. Estrogen Receptors , 2006, Pharmacological Reviews.

[4]  Heike Brand,et al.  Estrogen Receptor-α Directs Ordered, Cyclical, and Combinatorial Recruitment of Cofactors on a Natural Target Promoter , 2003, Cell.

[5]  M. Stallcup,et al.  Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Bert W O'Malley,et al.  Coregulator function: a key to understanding tissue specificity of selective receptor modulators. , 2004, Endocrine reviews.

[7]  J. Berger,et al.  Evolutionary relationships and structural mechanisms of AAA+ proteins. , 2006, Annual review of biophysics and biomolecular structure.

[8]  Brian D Strahl,et al.  Role of protein methylation in regulation of transcription. , 2005, Endocrine reviews.

[9]  Jérôme Eeckhoute,et al.  A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. , 2006, Genes & development.

[10]  B. Katzenellenbogen,et al.  Selective recognition of distinct classes of coactivators by a ligand-inducible activation domain. , 2004, Molecular cell.

[11]  W. Bremner,et al.  Advances in male contraception. , 2008, Endocrine reviews.

[12]  R. Gaynor,et al.  Formation of an IKKalpha-dependent transcription complex is required for estrogen receptor-mediated gene activation. , 2005, Molecular cell.

[13]  S. Safe,et al.  Cell context-dependent differences in the induction of E2F-1 gene expression by 17 beta-estradiol in MCF-7 and ZR-75 cells. , 2003, Endocrinology.

[14]  B. O’Malley,et al.  Signaling within a Coactivator Complex: Methylation of SRC-3/AIB1 Is a MolecularSwitch for Complex Disassembly , 2006, Molecular and Cellular Biology.

[15]  K. Coser,et al.  Global analysis of ligand sensitivity of estrogen inducible and suppressible genes in MCF7/BUS breast cancer cells by DNA microarray , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Barry Komm,et al.  Estrogen-regulated gene networks in human breast cancer cells: involvement of E2F1 in the regulation of cell proliferation. , 2007, Molecular endocrinology.

[17]  Rakesh Kumar,et al.  Steroid hormone receptor signaling in tumorigenesis , 2005, Journal of cellular biochemistry.

[18]  H. Kinyamu,et al.  Changes in attitude, changes in latitude: nuclear receptors remodeling chromatin to regulate transcription. , 2006, Molecular endocrinology.

[19]  T. Baker,et al.  Remodeling protein complexes: Insights from the AAA+ unfoldase ClpX and Mu transposase , 2005, Protein science : a publication of the Protein Society.

[20]  J. Wong,et al.  A role for cofactor–cofactor and cofactor–histone interactions in targeting p300, SWI/SNF and Mediator for transcription , 2003, The EMBO journal.

[21]  L. Freedman,et al.  Reciprocal Recruitment of DRIP/Mediator and p160 Coactivator Complexes in Vivo by Estrogen Receptor* , 2002, The Journal of Biological Chemistry.

[22]  M. Louie,et al.  Direct Control of Cell Cycle Gene Expression by Proto-Oncogene Product ACTR, and Its Autoregulation Underlies Its Transforming Activity , 2006, Molecular and Cellular Biology.

[23]  A. Klein-Szanto,et al.  E2F-1: a proliferative marker of breast neoplasia. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[24]  M. O’Donnell,et al.  The replication clamp-loading machine at work in the three domains of life , 2006, Nature Reviews Molecular Cell Biology.

[25]  M. Louie,et al.  ACTR/AIB1 Functions as an E2F1 Coactivator To Promote Breast Cancer Cell Proliferation and Antiestrogen Resistance , 2004, Molecular and Cellular Biology.

[26]  Robert L Sutherland,et al.  Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. , 2005, Endocrine-related cancer.

[27]  A. Papanikolaou,et al.  Cyclin D1 in breast cancer pathogenesis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  J. Yates,et al.  A methylation-mediator complex in hormone signaling. , 2004, Genes & development.

[29]  R. Evans,et al.  Regulation of Hormone-Induced Histone Hyperacetylation and Gene Activation via Acetylation of an Acetylase , 1999, Cell.

[30]  Céline Lefebvre,et al.  From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  T. Rapoport,et al.  JCB Article , 2001 .

[32]  H. Hurst,et al.  Targeting of SWI/SNF chromatin remodelling complexes to estrogen‐responsive genes , 2002, The EMBO journal.

[33]  K. Korach,et al.  Lessons in estrogen biology from knockout and transgenic animals. , 2005, Annual review of physiology.

[34]  V. Giguère,et al.  Coregulators of estrogen receptor action. , 2002, Critical reviews in eukaryotic gene expression.

[35]  Thomas E. Curry,et al.  Molecular Endocrinology , 2009, Methods in Molecular Biology.

[36]  Marc Montminy,et al.  A Transcriptional Switch Mediated by Cofactor Methylation , 2001, Science.

[37]  B. Chait,et al.  MED1/TRAP220 exists predominantly in a TRAP/ Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription. , 2005, Molecular cell.

[38]  J. Foekens,et al.  Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer , 2005, The Lancet.

[39]  I. Ellis,et al.  A consensus prognostic gene expression classifier for ER positive breast cancer , 2006, Genome Biology.

[40]  Margaret Gardiner-Garden,et al.  c-Myc overexpression and endocrine resistance in breast cancer , 2006, The Journal of Steroid Biochemistry and Molecular Biology.

[41]  F. Stossi,et al.  Whole-Genome Cartography of Estrogen Receptor α Binding Sites , 2007, PLoS genetics.

[42]  W. Kraus,et al.  Transcriptional activation by nuclear receptors. , 2004, Essays in biochemistry.

[43]  Martin C Frith,et al.  Genomic targets of nuclear estrogen receptors. , 2004, Molecular endocrinology.

[44]  P. Hanson,et al.  AAA+ proteins: have engine, will work , 2005, Nature Reviews Molecular Cell Biology.

[45]  C. Glass,et al.  Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. , 2006, Genes & development.

[46]  Clifford A. Meyer,et al.  Chromosome-Wide Mapping of Estrogen Receptor Binding Reveals Long-Range Regulation Requiring the Forkhead Protein FoxA1 , 2005, Cell.

[47]  Barry Komm,et al.  Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. , 2003, Endocrinology.

[48]  Myles Brown,et al.  Cofactor Dynamics and Sufficiency in Estrogen Receptor–Regulated Transcription , 2000, Cell.

[49]  Urs Eppenberger,et al.  Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome , 2007, Breast Cancer Research.