Histone deacetylase 6 (HDAC) 6 is a regulatory factor in the endocrine traffic network that controls growth factor receptor stability. Histone deacetylase 6 expression and its pathogenic role in the uterine leiomyoma have not been studied. Here, we demonstrated that there was a consistent pattern of increasing HDAC6 and estrogen receptor (ER) α expression in leiomyoma samples. For all individual cases, expression of HDAC6 in the normal myometrium or leiomyoma positively correlated with ERα expression. The spearman’s rho (ρ) was .53 (P = .008) between HDAC6 and ERα in normal myometrium and, more significantly, the spearman rho was .80 (P < .001) between HDAC6 and ERα in leiomyoma. In ELT-3 leiomyoma cells, silencing HDAC6 expression substantially reduced ERα expression, lowered estrogen response, and inhibited ELT-3 cell growth. Our results, taken together, are the first to provide experimental evidence suggesting that HDAC6 may be an essential molecular therapeutic target in controlling leiomyoma growth.
MarshallLMSpiegelmanDBarbieriRL. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol. 1997;90(6):967–973.
2.
ParkerWH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007;87(4):725–736.
3.
JacobsonGFShaberREArmstrongMAHungYY. Changes in rates of hysterectomy and uterine conserving procedures for treatment of uterine leiomyoma. Am J Obstet Gynecol. 2007;196(6):601 e1–e5.
BakasPLiapisAVlahopoulosS. Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness. Fertil Steril. 2008;90(5):1878–1885.
13.
KovacsKAOszterAGoczePMKornyeiJLSzaboI. Comparative analysis of cyclin D1 and oestrogen receptor (alpha and beta) levels in human leiomyoma and adjacent myometrium. Mol Hum Reprod. 2001;7(11):1085–1091.
14.
Al-HendyALeeEJWangHQCoplandJA. Gene therapy of uterine leiomyomas: adenovirus-mediated expression of dominant negative estrogen receptor inhibits tumor growth in nude mice. Am J Obstet Gynecol. 2004;191(5):1621–1631.
15.
de RuijterAJvan GennipAHCaronHNKempSvan KuilenburgAB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370(pt 3):737–749.
16.
ChoudharyCKumarCGnadF. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325(5942):834–840.
17.
VerdelAKhochbinS. Identification of a new family of higher eukaryotic histone deacetylases. Coordinate expression of differentiation-dependent chromatin modifiers. J Biol Chem. 1999;274(4):2440–2445.
18.
HubbertCGuardiolaAShaoR. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417(6887):455–458.
19.
KawaguchiYKovacsJJMcLaurinAVanceJMItoAYaoTP. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 2003;115(6):727–738.
20.
KovacsJJMurphyPJGaillardS. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell. 2005;18(5):601–607.
FlissAEBenzenoSRaoJCaplanAJ. Control of estrogen receptor ligand binding by Hsp90. J Steroid Biochem Mol Biol. 2000;72(5):223–230.
23.
HoweSRGottardisMMEverittJIGoldsworthyTLWolfDCWalkerC. Rodent model of reproductive tract leiomyomata. Establishment and characterization of tumor-derived cell lines. Am J Pathol. 1995;146(6):1568–1579.
24.
BoulvenIPalmierBRobinPVacherMHarbonSLeiberD. Platelet-derived growth factor stimulates phospholipase C-gamma1, extracellular signal-regulated kinase, and arachidonic acid release in rat myometrial cells: contribution to cyclic 3’,5'-adenosine monophosphate production and effect on cell proliferation. Biol Reprod. 2001;65(2):496–506.
25.
Fuchs-YoungRHoweSHaleLMilesRWalkerC. Inhibition of estrogen-stimulated growth of uterine leiomyomas by selective estrogen receptor modulators. Mol Carcinog. 1996;17(3):151–159.
26.
LubahnDBMoyerJSGoldingTSCouseJFKorachKSSmithiesO. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci U S A. 1993;90(23):11162–1166.
AlaoJPLamEWAliS. Histone deacetylase inhibitor trichostatin A represses estrogen receptor alpha-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines. Clin Cancer Res. 2004;10(23):8094–8104.
29.
ReidGMetivierRLinCY. Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor alpha, in response to deacetylase inhibition by valproic acid and trichostatin A. Oncogene. 2005;24(31):4894–4907.
30.
WhitesellLLindquistSL. HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005;5(10):761–772.
31.
HuaKTWayTDLinJK. Pentagalloylglucose inhibits estrogen receptor alpha by lysosome-dependent depletion and modulates ErbB/PI3K/Akt pathway in human breast cancer MCF-7 cells. Mol Carcinog. 2006;45(8):551–560.
32.
EnglundKBlanckAGustavssonI. Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment. J Clin Endocrinol Metab. 1998;83(11):4092–4096.
33.
VuKGreenspanDLWuTCZacurHAKurmanRJ. Cellular proliferation, estrogen receptor, progesterone receptor, and bcl-2 expression in GnRH agonist-treated uterine leiomyomas. Hum Pathol. 1998;29(4):359–363.
34.
ScialliARLeviAJ. Intermittent leuprolide acetate for the nonsurgical management of women with leiomyomata uteri. Fertil Steril. 2000;74(3):540–546.
35.
BazzaroMLinZSantillanA. Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor. Clin Cancer Res. 2008;14(22):7340–7347.
