title: HMBA is a putative HSP70 activator stimulating HEXIM1 expression that is down-regulated by estrogen.
abstract: Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is identified as a novel inhibitor of estrogen stimulated breast cell growth, and it suppresses estrogen receptor-α transcriptional activity. HEXIM1 protein level has been found to be downregulated by estrogens. Recently, HEXIM1 has been found to inhibit androgen receptor transcriptional activity as well. Researchers have used Hexamethylene bis-acetamide (HMBA) for decades to stimulate HEXIM1 expression, which also inhibit estrogen stimulated breast cancer cell gene activation and androgen stimulated prostate cancer gene activation. However, the direct molecular targets of HMBA that modulate the induction of HEXIM1 expression in mammalian cells have not been identified. Based on HMBA and its more potent analog 4a1, we designed molecular probes to pull down the binding proteins of these compounds. Via proteomic approach and biological assays, we demonstrate that HMBA and 4a1 are actually heat shock protein 70 (HSP70) binders. The known HSP70 activator showed similar activity as HMBA and 4a1 to induce HEXIM1 expression, suggesting that HMBA and 4a1 might be putative HSP70 activators. Molecular target identification of HMBA and 4a1 could lead to further structural optimization of the parental compound to generate more potent derivatives to stimulate HEXIM1 expression, which could be a novel approach for hormone dependent breast cancer and prostate cancer treatment.
authors.affiliation: Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH, 44115, USA.
authors.forename: Rati
authors.initials: R
authors.lastname: Lama
authors.affiliation: College of Chemistry and Material Science, Key Laboratory of Beibu Gulf Environment Change and Resources Utilization, Guangxi Teachers Education University, Nanning 530001, China.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Gan
authors.affiliation: Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH, 44115, USA.
authors.forename: Nethrie
authors.initials: N
authors.lastname: Idippily
authors.affiliation: Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH, 44115, USA.
authors.forename: Viharika
authors.initials: V
authors.lastname: Bobba
authors.affiliation: Division of General Medical Science-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: David
authors.initials: D
authors.lastname: Danielpour
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Montano
authors.affiliation: Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH, 44115, USA. Electronic address: B.su@csuohio.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Su
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D044482:Benzeneacetamides / Q000737:chemistry*; D019921:Biotinylation; D001943:Breast Neoplasms / Q000188:drug therapy; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D040901:Proteomics; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D014157:Transcription Factors
chemical_list: D000081:Acetamides; D044482:Benzeneacetamides; D004967:Estrogens; C476123:HEXIM1 protein, human; D018840:HSP70 Heat-Shock Proteins; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; C014026:hexamethylene bisacetamide
keywords: Estrogen receptor; HEXIM1; HMBA; HSP70; Target identification