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Article

HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α

  • Authors:
    • Tomohiko Fukuda
    • Akira Shirane
    • Osamu Wada‑Hiraike
    • Katsutoshi Oda
    • Michihiro Tanikawa
    • Ayako Sakuabashi
    • Mana Hirano
    • Houju Fu
    • Yoshihiro Morita
    • Yuichiro Miyamoto
    • Kanako Inaba
    • Kei Kawana
    • Yutaka Osuga
    • Tomoyuki Fujii
  • View Affiliations / Copyright

    Affiliations: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113‑8655, Japan
  • Pages: 5538-5544
    |
    Published online on: July 9, 2015
       https://doi.org/10.3892/mmr.2015.4070
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Abstract

A previous study demonstrated that the progesterone‑inducible HAND2 gene product is a basic helix‑loop‑helix transcription factor and prevents mitogenic effects of estrogen receptor α (ERα) by inhibiting fibroblast growth factor signalling in mouse uteri. However, whether HAND2 directly affects the transcriptional activation function of ERα remains to be elucidated. In the present study, the physical interaction between HAND2 and ERα was investigating by performing an immunoprecipitation assay and an in vitro pull‑down assay. The results demonstrated that HAND2 and ERα interacted in a ligand‑independent manner. The in vitro pull‑down assays revealed a direct interaction between HAND2 and the amino‑terminus of ERα, termed the activation function‑1 domain. To determine the physiological significance of this interaction, the role of HAND2 as a cofactor of ERα was investigated, which revealed that HAND2 inhibited the ligand‑dependent transcriptional activation function of ERα. This result was further confirmed and the mRNA expression of vascular endothelial growth factor, an ERα‑downstream factor, was decreased by the overexpression of HAND2. This inhibition of ligand‑dependent transcriptional activation function of ERα was possibly attributed to the proteasomic degradation of ERα by HAND2. These results indicate a novel anti‑tumorigenic function of HAND2 in regulating ERα‑dependent gene expression. Considering that HAND2 is commonly hypermethylated and silenced in endometrial cancer, it is hypothesized that HAND2 may serve as a possible tumor suppressor, particularly in uterine tissue.
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1 

SGO Clinical Practice Endometrial Cancer Working Group; Burke WM, Orr J, Leitao M, Salom E, Gehrig P, Olawaiye AB, Brewer M, Boruta D, Villella J, et al: Endometrial cancer: A review and current management strategies: Part I. Gynecol Oncol. 134:385–392. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 15:10–17. 1983. View Article : Google Scholar : PubMed/NCBI

3 

Hecht JL and Mutter GL: Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol. 24:4783–4791. 2006. View Article : Google Scholar : PubMed/NCBI

4 

Henderson BE, Casagrande JT, Pike MC, Mack T, Rosario I and Duke A: The epidemiology of endometrial cancer in young women. Br J Cancer. 47:749–756. 1983. View Article : Google Scholar : PubMed/NCBI

5 

Koskas M, Uzan J, Luton D, Rouzier R and Daraï E: Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma: Systematic review and meta-analysis. Fertil Steril. 101:785–794. 2014. View Article : Google Scholar : PubMed/NCBI

6 

Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, et al: Menopausal hormone therapy and health outcomes during the intervention and extended post-stopping phases of the Women's Health Initiative randomized trials. JAMA. 310:1353–1368. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Hollenberg SM, Sternglanz R, Cheng PF and Weintraub H: Identification of a new family of tissue-specific basic helix-loop-helix proteins with a two-hybrid system. Mol Cell Biol. 15:3813–3822. 1995.PubMed/NCBI

8 

Firulli AB: A HANDful of questions: The molecular biology of the heart and neural crest derivatives (HAND)-subclass of basic helix-loop-helix transcription factors. Gene. 312:27–40. 2003. View Article : Google Scholar : PubMed/NCBI

9 

Dai YS, Cserjesi P, Markham BE and Molkentin JD: The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism. J Biol Chem. 277:24390–24398. 2002. View Article : Google Scholar : PubMed/NCBI

10 

Yamagishi H, Yamagishi C, Nakagawa O, Harvey RP, Olson EN and Srivastava D: The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. Dev Biol. 239:190–203. 2001. View Article : Google Scholar

11 

Rychlik JL, Gerbasi V and Lewis EJ: The interaction between dHAND and Arix at the dopamine beta-hydroxylase promoter region is independent of direct dHAND binding to DNA. J Biol Chem. 278:49652–49660. 2003. View Article : Google Scholar : PubMed/NCBI

12 

Morikawa Y, Dai YS, Hao J, Bonin C, Hwang S and Cserjesi P: The basic helix-loop-helix factor Hand 2 regulates autonomic nervous system development. Dev Dyn. 234:613–621. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Firulli BA, Hadzic DB, McDaid JR and Firulli AB: The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function. J Biol Chem. 275:33567–33573. 2000. View Article : Google Scholar : PubMed/NCBI

14 

Dai YS and Cserjesi P: The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer. J Biol Chem. 277:12604–12612. 2002. View Article : Google Scholar : PubMed/NCBI

15 

Li Q, Kannan A, DeMayo FJ, Lydon JP, Cooke PS, Yamagishi H, Srivastava D, Bagchi MK, Bagchi IC, et al: The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science. 331:912–916. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Jones A, Teschendorff AE, Li Q, Hayward JD, Kannan A, Mould T, West J, Zikan M, Cibula D, Fiegl H, et al: Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development. PLoS Med. 10:e10015512013. View Article : Google Scholar : PubMed/NCBI

17 

Wada-Hiraike O, Yano T, Nei T, Matsumoto Y, Nagasaka K, Takizawa S, Oishi H, Arimoto T, Nakagawa S, Yasugi T, et al: The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor alpha. Br J Cancer. 92:2286–2291. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Koyama S, Wada-Hiraike O, Nakagawa S, Tanikawa M, Hiraike H, Miyamoto Y, Sone K, Oda K, Fukuhara H, Nakagawa K, et al: Repression of estrogen receptor beta function by putative tumor suppressor DBC1. Biochem Biophys Res Commun. 392:357–362. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Fu H, Wada-Hiraike O, Hirano M, Kawamura Y, Sakurabashi A, Shirane A, Morita Y, Isono W, Oishi H, Koga K, et al: SIRT3 positively regulates the expression of folliculogenesis- and luteinization-related genes and progesterone secretion by manipulating oxidative stress in human luteinized granulosa cells. Endocrinology. 155:3079–3087. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Hiraike H, Wada-Hiraike O, Nakagawa S, Koyama S, Miyamoto Y, Sone K, Tanikawa M, Tsuruga T, Nagasaka K, Matsumoto Y, et al: Identification of DBC1 as a transcriptional repressor for BRCA1. Br J Cancer. 102:1061–1067. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Cullinan-Bove K and Koos RD: Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: Rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology. 133:829–837. 1993.PubMed/NCBI

22 

Bersten DC, Sullivan AE, Peet DJ and Whitelaw ML: bHLH-PAS proteins in cancer. Nat Rev Cancer. 13:827–841. 2013. View Article : Google Scholar : PubMed/NCBI

23 

White TE and Gasiewicz TA: The human estrogen receptor structural gene contains a DNA sequence that binds activated mouse and human Ah receptors: A possible mechanism of estrogen receptor regulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Biophys Res Commun. 193:956–962. 1993. View Article : Google Scholar : PubMed/NCBI

24 

Ohtake F, Baba A, Takada I, Okada M, Iwasaki K, Miki H, Takahashi S, Kouzmenko A, Nohara K, Chiba T, et al: Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature. 446:562–566. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Swedenborg E and Pongratz I: AhR and ARNT modulate ER signaling. Toxicology. 268:132–138. 2010. View Article : Google Scholar

26 

Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, et al: Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature. 423:545–550. 2003. View Article : Google Scholar : PubMed/NCBI

27 

Welboren WJ, Sweep FC, Span PN and Stunnenberg HG: Genomic actions of estrogen receptor alpha: What are the targets and how are they regulated? Endocr Relat Cancer. 16:1073–1089. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Zhou W and Slingerland JM: Links between oestrogen receptor activation and proteolysis: Relevance to hormone-regulated cancer therapy. Nat Rev Cancer. 14:26–38. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID, et al: BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science. 284:1354–1356. 1999. View Article : Google Scholar : PubMed/NCBI

30 

Dirkx E, Gladka MM, Philippen LE, Armand AS, Kinet V, Leptidis S, El Azzouzi H, Salic K, Bourajjaj M, da Silva GJ, et al: Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure. Nat Cell Biol. 15:1282–1293. 2013. View Article : Google Scholar : PubMed/NCBI

31 

Yamagishi H, Garg V, Matsuoka R, Thomas T and Srivastava D: A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science. 283:1158–1161. 1999. View Article : Google Scholar : PubMed/NCBI

32 

Bondesson M, Hao R, Lin CY, Williams C and Gustafsson JA: Estrogen receptor signaling during vertebrate development. Biochim Biophys Acta. 1849:142–151. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL and Cummings SR: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 117:1016–1037. 1992. View Article : Google Scholar : PubMed/NCBI

34 

Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC and Taylor RN: Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci USA. 97:10972–10977. 2000. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Fukuda T, Shirane A, Wada‑Hiraike O, Oda K, Tanikawa M, Sakuabashi A, Hirano M, Fu H, Morita Y, Miyamoto Y, Miyamoto Y, et al: HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α. Mol Med Rep 12: 5538-5544, 2015.
APA
Fukuda, T., Shirane, A., Wada‑Hiraike, O., Oda, K., Tanikawa, M., Sakuabashi, A. ... Fujii, T. (2015). HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α. Molecular Medicine Reports, 12, 5538-5544. https://doi.org/10.3892/mmr.2015.4070
MLA
Fukuda, T., Shirane, A., Wada‑Hiraike, O., Oda, K., Tanikawa, M., Sakuabashi, A., Hirano, M., Fu, H., Morita, Y., Miyamoto, Y., Inaba, K., Kawana, K., Osuga, Y., Fujii, T."HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α". Molecular Medicine Reports 12.4 (2015): 5538-5544.
Chicago
Fukuda, T., Shirane, A., Wada‑Hiraike, O., Oda, K., Tanikawa, M., Sakuabashi, A., Hirano, M., Fu, H., Morita, Y., Miyamoto, Y., Inaba, K., Kawana, K., Osuga, Y., Fujii, T."HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α". Molecular Medicine Reports 12, no. 4 (2015): 5538-5544. https://doi.org/10.3892/mmr.2015.4070
Copy and paste a formatted citation
x
Spandidos Publications style
Fukuda T, Shirane A, Wada‑Hiraike O, Oda K, Tanikawa M, Sakuabashi A, Hirano M, Fu H, Morita Y, Miyamoto Y, Miyamoto Y, et al: HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α. Mol Med Rep 12: 5538-5544, 2015.
APA
Fukuda, T., Shirane, A., Wada‑Hiraike, O., Oda, K., Tanikawa, M., Sakuabashi, A. ... Fujii, T. (2015). HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α. Molecular Medicine Reports, 12, 5538-5544. https://doi.org/10.3892/mmr.2015.4070
MLA
Fukuda, T., Shirane, A., Wada‑Hiraike, O., Oda, K., Tanikawa, M., Sakuabashi, A., Hirano, M., Fu, H., Morita, Y., Miyamoto, Y., Inaba, K., Kawana, K., Osuga, Y., Fujii, T."HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α". Molecular Medicine Reports 12.4 (2015): 5538-5544.
Chicago
Fukuda, T., Shirane, A., Wada‑Hiraike, O., Oda, K., Tanikawa, M., Sakuabashi, A., Hirano, M., Fu, H., Morita, Y., Miyamoto, Y., Inaba, K., Kawana, K., Osuga, Y., Fujii, T."HAND2‑mediated proteolysis negatively regulates the function of estrogen receptor α". Molecular Medicine Reports 12, no. 4 (2015): 5538-5544. https://doi.org/10.3892/mmr.2015.4070
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