HMBA is a putative HSP70 activator stimulating HEXIM1 expression that is down-regulated by estrogen. Issue 168 (April 2017)

• Record Type: Journal Article
• Authors: Lama, Rati; Gan, Chunfang; Idippily, Nethrie; Bobba, Viharika; Danielpour, David; Montano, Monica; Su, Bin
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 168(2017)
• Page Start: 91
• Page End: 101
• Publication Date: 2017-04
• Subjects: HEXIM1 hexamethylene bis-acetamide inducible protein 1 -- HMBA hexamethylene bis-acetamide -- HSP70 heat shock protein 70 -- SAHA suberanilohydroxamic acid -- HDAC histone deacetylases -- SDS/PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis -- FBS fetal bovine serum -- PVDF polyvinylidene diflouride; HEXIM1 -- HMBA -- Target identification -- HSP70 -- Estrogen receptor; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.02.008
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: HEXIM1 is an estrogen receptor disrupting protein that could be induced by HMBA and 4a1. Two molecular probes based on HMBA and 4a1 are synthesized to identify the molecular target. HSP70 is identified as the binding protein of HMBA and 4a1via proteomic approach. HSP70 activator shows similar biological activity to HMBA and 4a1. 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.