Abstract
Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1α. Mel-18 negatively regulated the HIF-1α expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1α expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1α protein level. Mel-18 modulated the HIF-1α transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1α/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1α expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1α and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Al-Khouri AM, Ma Y, Togo SH, Williams S, Mustelin T . (2005). Cooperative phosphorylation of the tumor suppressor phosphatase and tensin homologue (PTEN) by casein kinases and glycogen synthase kinase 3beta. J Biol Chem 280: 35195–35202.
Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA et al. (1996). An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 93: 12969–12973.
Ashcroft M, Ludwig RL, Woods DB, Copeland TD, Weber HO, MacRae EJ et al. (2002). Phosphorylation of HDM2 by Akt. Oncogene 21: 1955–1962.
Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA et al. (2010). HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol 176: 2292–2301.
Bardos JI, Chau NM, Ashcroft M . (2004). Growth factor-mediated induction of HDM2 positively regulates hypoxia-inducible factor 1alpha expression. Mol Cell Biol 24: 2905–2914.
Brahimi-Horn MC, Pouyssegur J . (2009). HIF at a glance. J Cell Sci 122: 1055–1057.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.
Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC et al. (2000). Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275: 25733–25741.
Davis R, Singh KP, Kurzrock R, Shankar S . (2009). Sulforaphane inhibits angiogenesis through activation of FOXO transcription factors. Oncol Rep 22: 1473–1478.
Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K et al. (1999). Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J 18: 1905–1914.
Emerling BM, Weinberg F, Liu JL, Mak TW, Chandel NS . (2008). PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci USA 105: 2622–2627.
Fang J, Ding M, Yang L, Liu LZ, Jiang BH . (2007). PI3K/PTEN/AKT signaling regulates prostate tumor angiogenesis. Cell Signal 19: 2487–2497.
Flugel D, Gorlach A, Michiels C, Kietzmann T . (2007). Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. Mol Cell Biol 27: 3253–3265.
Guo BH, Zhang X, Zhang HZ, Lin HL, Feng Y, Shao JY et al. (2010). Low expression of Mel-18 predicts poor prognosis in patients with breast cancer. Ann Oncol 21: 2361–2369.
Guo WJ, Datta S, Band V, Dimri GP . (2007a). Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi-1 and c-Myc oncoproteins. Mol Biol Cell 18: 536–546.
Guo WJ, Zeng MS, Yadav A, Song LB, Guo BH, Band V et al. (2007b). Mel-18 acts as a tumor suppressor by repressing Bmi-1 expression and down-regulating Akt activity in breast cancer cells. Cancer Res 67: 5083–5089.
Hoffmann AC, Mori R, Vallbohmer D, Brabender J, Klein E, Drebber U et al. (2008). High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia 10: 674–679.
Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M . (1999). The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397: 164–168.
Jung JE, Lee HG, Cho IH, Chung DH, Yoon SH, Yang YM et al. (2005). STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J 19: 1296–1298.
Jung JH, Choi HJ, Maeng YS, Choi JY, Kim M, Kwon JY et al. (2010). Mel-18, a mammalian Polycomb gene, regulates angiogenic gene expression of endothelial cells. Biochem Biophys Res Commun 400: 523–530.
Kim HJ, Chung H, Yoo YG, Kim H, Lee JY, Lee MO et al. (2007). Inhibitor of DNA binding 1 activates vascular endothelial growth factor through enhancing the stability and activity of hypoxia-inducible factor-1alpha. Mol Cancer Res 5: 321–329.
Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC et al. (2005). DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7: 263–273.
Lee JY, Jang KS, Shin DH, Oh MY, Kim HJ, Kim Y et al. (2008). Mel-18 negatively regulates INK4a/ARF-independent cell cycle progression via Akt inactivation in breast cancer. Cancer Res 68: 4201–4209.
Lee YM, Lim JH, Chun YS, Moon HE, Lee MK, Huang LE et al. (2009). Nutlin-3, an Hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated inactivation of HIF-1alpha. Carcinogenesis 30: 1768–1775.
Li W, Tan D, Zhang Z, Liang JJ, Brown RE . (2008). Activation of Akt-mTOR-p70S6 K pathway in angiogenesis in hepatocellular carcinoma. Oncol Rep 20: 713–719.
Li X, Lin G, Wu B, Zhou X, Zhou K . (2007). Overexpression of PTEN induces cell growth arrest and apoptosis in human breast cancer ZR-75-1 cells. Acta Biochim Biophys Sin (Shanghai) 39: 745–750.
Ma J, Sawai H, Ochi N, Matsuo Y, Xu D, Yasuda A et al. (2009). PTEN regulates angiogenesis through PI3K/Akt/VEGF signaling pathway in human pancreatic cancer cells. Mol Cell Biochem 331: 161–171.
Maxwell PH, Pugh CW, Ratcliffe PJ . (2001a). Activation of the HIF pathway in cancer. Curr Opin Genet Dev 11: 293–299.
Maxwell PH, Pugh CW, Ratcliffe PJ . (2001b). Insights into the role of the von Hippel-Lindau gene product. A key player in hypoxic regulation. Exp Nephrol 9: 235–240.
Merritt WM, Nick AM, Carroll AR, Lu C, Matsuo K, Dumble M et al. (2010). Bridging the gap between cytotoxic and biologic therapy with metronomic topotecan and pazopanib in ovarian cancer. Mol Cancer Ther 9: 985–995.
Pugh CW, Ratcliffe PJ . (2003). The von Hippel-Lindau tumor suppressor, hypoxia-inducible factor-1 (HIF-1) degradation, and cancer pathogenesis. Semin Cancer Biol 13: 83–89.
Qian T, Lee JY, Park JH, Kim HJ, Kong G . (2010). Id1 enhances RING1b E3 ubiquitin ligase activity through the Mel-18/Bmi-1 polycomb group complex. Oncogene 29: 5818–5827.
Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q et al. (2000). Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14: 34–44.
Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J . (1999). p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 274: 32631–32637.
Skinner HD, Zheng JZ, Fang J, Agani F, Jiang BH . (2004). Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor 1alpha, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling. J Biol Chem 279: 45643–45651.
Tan M, Gu Q, He H, Pamarthy D, Semenza GL, Sun Y . (2008). SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1 alpha ubiquitination and degradation. Oncogene 27: 1404–1411.
Tanimoto K, Makino Y, Pereira T, Poellinger L . (2000). Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 19: 4298–4309.
Tian T, Nan KJ, Wang SH, Liang X, Lu CX, Guo H et al. (2010). PTEN regulates angiogenesis and VEGF expression through phosphatase-dependent and -independent mechanisms in HepG2 cells: PTEN regulates angiogenesis in HepG2. Carcinogenesis 31: 1211–1219.
Torres J, Pulido R . (2001). The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem 276: 993–998.
Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H et al. (2007). Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128: 141–156.
Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M . (2004). Stem cells and cancer; the polycomb connection. Cell 118: 409–418.
Van Themsche C, Leblanc V, Parent S, Asselin E . (2009). X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization. J Biol Chem 284: 20462–20466.
Vemula S, Shi J, Hanneman P, Wei L, Kapur R . (2010). ROCK1 functions as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Blood 115: 1785–1796.
Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z et al. (2007). NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128: 129–139.
Xiong H, Wang D, Chen L, Choo YS, Ma H, Tang C et al. (2009). Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest 119: 650–660.
Yee Koh M, Spivak-Kroizman TR, Powis G . (2008). HIF-1 regulation: not so easy come, easy go. Trends Biochem Sci 33: 526–534.
Yoo YG, Yeo MG, Kim DK, Park H, Lee MO . (2004). Novel function of orphan nuclear receptor Nur77 in stabilizing hypoxia-inducible factor-1alpha. J Biol Chem 279: 53365–53373.
Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM et al. (2000). Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60: 1541–1545.
Acknowledgements
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (No. 2010K001350 and 2010-0020534).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Park, JH., Lee, JY., Shin, DH. et al. Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway. Oncogene 30, 4578–4589 (2011). https://doi.org/10.1038/onc.2011.174
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2011.174
Keywords
This article is cited by
-
Extracellular Vesicles from Human Umbilical Cord Mesenchymal Stem Cells Facilitate Diabetic Wound Healing Through MiR-17-5p-mediated Enhancement of Angiogenesis
Stem Cell Reviews and Reports (2022)
-
AKT-mediated regulation of chromatin ubiquitylation and tumorigenesis through Mel18 phosphorylation
Oncogene (2021)
-
LncRNA-HNF1A-AS1 functions as a competing endogenous RNA to activate PI3K/AKT signalling pathway by sponging miR-30b-3p in gastric cancer
British Journal of Cancer (2020)
-
LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis
Oncogene (2017)
-
Context-dependent actions of Polycomb repressors in cancer
Oncogene (2016)