Epigenetic regulation of embryonic stem cell marker miR302C in human chondrosarcoma as determinant of antiproliferative activity of proline-rich polypeptide 1

Galoian,Karina; Qureshi,Amir; D'Ippolito,Gianluca; Schiller,Paul  C.; Molinari,Marco; Johnstone,Andrea  L.; Brothers,Shaun P.; Paz,Ana  C.; Temple,H. T.

doi:10.3892/ijo.2015.3054

Epigenetic regulation of embryonic stem cell marker miR302C in human chondrosarcoma as determinant of antiproliferative activity of proline-rich polypeptide 1

Authors:
- Karina Galoian
- Amir Qureshi
- Gianluca D'Ippolito
- Paul C. Schiller
- Marco Molinari
- Andrea L. Johnstone
- Shaun P. Brothers
- Ana C. Paz
- H. T. Temple
View Affiliations

Affiliations: Department of Orthopaedic Surgery, University of Miami Miller School of Medicine, Miami, FL, USA, Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA, Division of Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
Published online on: June 18, 2015 https://doi.org/10.3892/ijo.2015.3054
Pages: 465-472
Copyright: © Galoian et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Metastatic chondrosarcoma of mesenchymal origin is the second most common bone malignancy and does not respond either to chemotherapy or radiation; therefore, the search for new therapies is relevant and urgent. We described recently that tumor growth inhibiting cytostatic proline-rich polypeptide 1, (PRP-1) significantly upregulated tumor suppressor miRNAs, downregulated onco-miRNAs in human chondrosarcoma JJ012 cell line, compared to chondrocytes culture. In this study we hypothesized the existence and regulation of a functional marker in cancer stem cells, correlated to peptides antiproliferative activity. Experimental results indicated that among significantly downregulated miRNA after PRP-1treatment was miRNAs 302c*. This miRNA is a part of the cluster miR302‑367, which is stemness regulator in human embryonic stem cells and in certain tumors, but is not expressed in adult hMSCs and normal tissues. PRP-1 had strong inhibitory effect on viability of chondrosarcoma and multilineage induced multipotent adult cells (embryonic primitive cell type). Unlike chondrosarcoma, in glioblastoma, PRP-1 does not have any inhibitory activity on cell proliferation, because in glioblastoma miR-302-367 cluster plays an opposite role, its expression is sufficient to suppress the stemness inducing properties. The observed correlation between the antiproliferative activity of PRP-1 and its action on downregulation of miR302c explains the peptides opposite effects on the upregulation of proliferation of adult mesenchymal stem cells, and the inhibition of the proliferation of human bone giant-cell tumor stromal cells, reported earlier. PRP-1 substantially downregulated the miR302c targets, the stemness markers Nanog, c-Myc and polycomb protein Bmi-1. miR302c expression is induced by JMJD2-mediated H3K9me2 demethylase activity in its promoter region. JMJD2 was reported to be a positive regulator for Nanog. Our experimental results proved that PRP-1 strongly inhibited H3K9 activity comprised of a pool of JMJD1 and JMJD2. We conclude that inhibition of H3K9 activity by PRP-1 leads to downregulation of miR302c and its targets, defining the PRP-1 antiproliferative role.

View Figures

View References

1	Ozaki T, Hillmann A, Lindner N, Blasius S and Winkelmann W: Metastasis of chondrosarcoma. J Cancer Res Clin Oncol. 122:625–628. 1996. View Article : Google Scholar : PubMed/NCBI
2	Galoian K, Temple TH and Galoyan A: Cytostatic effect of the hypothalamic cytokine PRP-1 is mediated by mTOR and cMyc inhibition in high grade chondrosarcoma. Neurochem Res. 36:812–818. 2011. View Article : Google Scholar : PubMed/NCBI
3	Galoian KA, Temple HT and Galoyan AA: mTORC1 inhibition and ECM-cell adhesion-independent drug resistance via PI3K-AKT and PI3K-RAS-MAPK feedback loops. Tumour Biol. 33:885–890. 2012. View Article : Google Scholar : PubMed/NCBI
4	Galoian KA, Temple TH and Galoyan A: Cytostatic effect of novel mTOR inhibitor, PRP-1 (galarmin) in MDA 231 (ER-) breast carcinoma cell line. PRP-1 inhibits mesenchymal tumors. Tumour Biol. 32:745–751. 2011. View Article : Google Scholar : PubMed/NCBI
5	Galoian KA, Guettouche T, Issac B, Qureshi A and Temple HT: Regulation of onco and tumor suppressor MiRNAs by mTORC1 inhibitor PRP-1 in human chondrosarcoma. Tumour Biol. 35:2335–2341. 2014. View Article : Google Scholar
6	Suh MR, Lee Y, Kim JY, Kim SK, Moon SH, Lee JY, Cha KY, Chung HM, Yoon HS, Moon SY, et al: Human embryonic stem cells express a unique set of microRNAs. Dev Biol. 270:488–498. 2004. View Article : Google Scholar : PubMed/NCBI
7	Barroso-del Jesus A, Lucena-Aguilar G and Menendez P: The miR-302-367 cluster as a potential stemness regulator in ESCs. Cell Cycle. 8:394–398. 2009. View Article : Google Scholar : PubMed/NCBI
8	Barroso-delJesus A, Romero-López C, Lucena-Aguilar G, Melen GJ, Sanchez L, Ligero G, Berzal-Herranz A and Menendez P: Embryonic stem cell-specific miR302-367 cluster: Human gene structure and functional characterization of its core promoter. Mol Cell Biol. 28:6609–6619. 2008. View Article : Google Scholar : PubMed/NCBI
9	Zhang B, Pan X and Anderson TA: MicroRNA: A new player in stem cells. J Cell Physiol. 209:266–269. 2006. View Article : Google Scholar : PubMed/NCBI
10	Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W, Gruber PJ, Epstein JA, et al: Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell. 8:376–388. 2011. View Article : Google Scholar : PubMed/NCBI
11	Kim J, Chu J, Shen X, Wang J and Orkin SH: An extended transcriptional network for pluripotency of embryonic stem cells. Cell. 132:1049–1061. 2008. View Article : Google Scholar : PubMed/NCBI
12	Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, et al: Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 478:529–533. 2011. View Article : Google Scholar : PubMed/NCBI
13	Pastori C, Daniel M, Penas C, et al: BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics. 9:611–620. 2014. View Article : Google Scholar : PubMed/NCBI
14	D’Ippolito G, Howard GA, Roos BA and Schiller PC: Sustained stromal stem cell self-renewal and osteoblastic differentiation during aging. Rejuvenation Res. 9:10–19. 2006. View Article : Google Scholar
15	D’Ippolito G, Diabira S, Howard GA, Menei P, Roos BA and Schiller PC: Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci. 117:2971–2981. 2004. View Article : Google Scholar
16	Galoian K, Scully S, McNamara G, Flynn P and Galoyan A: Antitumorigenic effect of brain proline-rich polypeptide-1 in human chondrosarcoma. Neurochem Res. 34:2117–2121. 2009. View Article : Google Scholar : PubMed/NCBI
17	Fareh M, Turchi L, Virolle V, Debruyne D, Almairac F, de-la-Forest Divonne S, Paquis P, Preynat-Seauve O, Krause KH, Chneiweiss H, et al: The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network. Cell Death Differ. 19:232–244. 2012. View Article : Google Scholar :
18	Chailakhyan RK, Gerasimov YV, Chailakhyan MR and Galoyan AA: Proline-rich hypothalamic polypeptide has opposite effects on the proliferation of human normal bone marrow stromal cells and human giant-cell tumour stromal cells. Neurochem Res. 35:934–939. 2010. View Article : Google Scholar : PubMed/NCBI
19	Lee MR, Prasain N, Chae HD, Kim YJ, Mantel C, Yoder MC and Broxmeyer HE: Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming. Stem Cells. 31:666–681. 2013. View Article : Google Scholar
20	Molofsky AV, Pardal R and Morrison SJ: Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol. 16:700–707. 2004. View Article : Google Scholar : PubMed/NCBI
21	Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P and Wicha MS: Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 66:6063–6071. 2006. View Article : Google Scholar : PubMed/NCBI
22	Jiang L, Li J and Song L: Bmi-1, stem cells and cancer. Acta Biochim Biophys Sin (Shanghai). 41:527–534. 2009. View Article : Google Scholar
23	Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, Cao L, Baiazitov R, Du W, Sydorenko N, et al: Selfrenewal as a therapeutic target in human colorectal cancer. Nat Med. 20:29–36. 2014. View Article : Google Scholar
24	Bonasio R, Lecona E, Narendra V, Voigt P, Parisi F, Kluger Y and Reinberg D: Interactions with RNA direct the Polycomb group protein SCML2 to chromatin where it represses target genes. eLife. 3:e026372014. View Article : Google Scholar : PubMed/NCBI
25	Galoian K, Qureshi A, Wideroff G and Temple HT: Restoration of desmosomal junction protein expression and inhibition of H3K9-specific histone demethylase activity by cytostatic proline-rich polypeptide-1 leads to suppression of tumorigenic potential in human chondrosarcoma cells. Mol Clin Oncol. 3:171–178. 2015.
26	Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E and Chang HY: Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell. 2:333–344. 2008. View Article : Google Scholar : PubMed/NCBI
27	Galoian K, Scully S and Galoyan A: Myc-oncogene inactivating effect by proline-rich polypeptide (PRP-1) in chondrosarcoma JJ012 cells. Neurochem Res. 34:379–385. 2009. View Article : Google Scholar
28	Irby RB and Yeatman TJ: Role of Src expression and activation in human cancer. Oncogene. 19:5636–5642. 2000. View Article : Google Scholar : PubMed/NCBI
29	Clarke MF and Fuller M: Stem cells and cancer: Two faces of eve. Cell. 124:1111–1115. 2006. View Article : Google Scholar : PubMed/NCBI
30	Durand B, Gao FB and Raff M: Accumulation of the cyclin-dependent kinase inhibitor p27/Kip1 and the timing of oligodendrocyte differentiation. EMBO J. 16:306–317. 1997. View Article : Google Scholar : PubMed/NCBI
31	Yadav V, Sultana S, Yadav J and Saini N: Gatifloxacin induces S- and G2-phase cell cycle arrest in pancreatic cancer cells via p21/p27/p53. PLoS One. 7:e477962012. View Article : Google Scholar
32	Jang TJ, Kang MS, Kim H, Kim DH, Lee JI and Kim JR: Increased expression of cyclin D1, cyclin E and p21(Cip1) associated with decreased expression of p27(Kip1) in chemically induced rat mammary carcinogenesis. Jpn J Cancer Res. 91:1222–1232. 2000. View Article : Google Scholar : PubMed/NCBI
33	Nadeem L, Brkic J, Chen YF, Bui T, Munir S and Peng C: Cytoplasmic mislocalization of p27 and CDK2 mediates the anti-migratory and antiproliferative effects of Nodal in human trophoblast cells. J Cell Sci. 126:445–453. 2013. View Article : Google Scholar
34	Cloos PA, Christensen J, Agger K and Helin K: Erasing the methyl mark: Histone demethylases at the center of cellular differentiation and disease. Genes Dev. 22:1115–1140. 2008. View Article : Google Scholar : PubMed/NCBI
35	Loh YH, Zhang W, Chen X, George J and Ng HH: Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev. 21:2545–2557. 2007. View Article : Google Scholar : PubMed/NCBI
36	Wang J, Park JW, Drissi H, Wang X and Xu RH: Epigenetic regulation of miR-302 by JMJD1C inhibits neural differentiation of human embryonic stem cells. J Biol Chem. 289:2384–2395. 2014. View Article : Google Scholar :
37	Abrahamyan SS, Davtyan TK, Khachatryan AR, Tumasyan NV, Sahakyan IK, Harutyunyan HA, Chailyan SG and Galoyan AA: Quantification of the hypothalamic proline-rich polypeptide 1in rat blood serum. Neurochem J. 8:38–43. 2014. View Article : Google Scholar