BRCA1-associated protein inhibits glioma cell proliferation and migration and glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway.

Publisher: Springer Country of Publication: Netherlands NLM ID: 101552938 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-3436 (Electronic) Linking ISSN: 22113428 NLM ISO Abbreviation: Cell Oncol (Dordr) Subsets: MEDLINE

Original Publication: Dordrecht : Springer

Cell Movement/*genetics ; Cell Proliferation/*genetics ; Glioma/*genetics ; Neoplastic Stem Cells/*metabolism ; Proteins/*metabolism ; Ubiquitin-Protein Ligases/*genetics; Animals ; Cell Line, Tumor ; Cell Self Renewal ; Female ; Gene Expression Regulation, Neoplastic ; Glioma/metabolism ; Glioma/therapy ; Humans ; Kaplan-Meier Estimate ; Male ; Mice, Inbred BALB C ; Mice, Nude ; Middle Aged ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; Transforming Growth Factor beta/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Xenograft Model Antitumor Assays

Purpose: BRCA1-associated protein (BRAP) was first identified by its ability to bind to the nuclear localization signalling motif of BRCA1 and other proteins. Subsequently, human BRAP has been found to exert multiple functions, many of which are related to cancer development. Up till now, however, the role of BRAP in glioma development has remained obscure. Here, we report a role for BRAP in mediating the proliferation and migration of glioma cells both in vitro and in vivo.
Methods: The expression of BRAP in 98 glioma patient samples was determined by immunohistochemistry, after which associations between BRAP expression and patient prognosis were assessed. A short hairpin RNA (shRNA) was used to knock down BRAP and an expression vector was used to exogenously overexpress BRAP in glioma cells. The effects of BRAP expression on tumour cell behaviour in vitro and in an in vivo xenograft mouse model were examined.
Results: We found that in glioma patients BRAP expression was associated with a favourable prognosis. We also found that shRNA-mediated knockdown of BRAP facilitated the proliferation and migration of glioma cells and the self-renewal of glioma stem cells. In parallel, we found that BRAP knockdown increased tumour growth and invasion and decreased survival in an in vivo glioma xenograft mouse model. Mechanistically, we found that BRAP inhibited glioma cell proliferation and migration, as well as glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway.
Conclusions: Together, our findings identify BRAP as a mediator of glioma cell proliferation, migration and glioma stem cell self-renewal.

Diab Vasc Dis Res. 2013 May;10(3):202-7. (PMID: 22965072)
Trends Biochem Sci. 2013 Dec;38(12):612-20. (PMID: 24239264)
Nat Commun. 2015 Jul 07;6:7138. (PMID: 26151821)
Cell Oncol (Dordr). 2017 Oct;40(5):471-482. (PMID: 28643230)
Cell Oncol (Dordr). 2017 Jun;40(3):247-261. (PMID: 28401486)
Ann Oncol. 2014 Sep;25 Suppl 3:iii93-101. (PMID: 24782454)
FASEB J. 2010 May;24(5):1454-66. (PMID: 20040518)
Gastroenterology. 2017 Nov;153(5):1304-1319.e5. (PMID: 28780075)
Nat Genet. 2009 Mar;41(3):329-33. (PMID: 19198608)
Neurol Clin. 2016 Nov;34(4):981-998. (PMID: 27720005)
Pharmacol Ther. 2014 May;142(2):164-75. (PMID: 24333502)
Nat Rev Cancer. 2015 Jan;15(1):7-24. (PMID: 25533673)
Trends Cell Biol. 2019 Mar;29(3):212-226. (PMID: 30594349)
Ann Oncol. 2010 Apr;21(4):683-91. (PMID: 19713247)
Med Oncol. 2013 Jun;30(2):541. (PMID: 23526420)
Methods Enzymol. 2006;407:237-47. (PMID: 16757328)
Cancer. 2015 Feb 15;121(4):502-16. (PMID: 25250735)
Biochim Biophys Acta. 2013 Dec;1833(12):3436-3444. (PMID: 23707952)
Mol Med. 2011 Sep-Oct;17(9-10):1065-74. (PMID: 21670849)
Nature. 2004 Jan 15;427(6971):256-60. (PMID: 14724641)
Prog Neurol Surg. 2018;30:1-11. (PMID: 29241168)
Nat Rev Cancer. 2018 Feb;18(2):128-134. (PMID: 29326430)
Mol Cell Biol. 2004 Sep;24(18):8236-43. (PMID: 15340083)
J Biol Chem. 2008 May 9;283(19):12789-96. (PMID: 18332145)
J Biol Chem. 2012 Dec 14;287(51):43007-18. (PMID: 23105109)
J Biol Chem. 1998 Mar 13;273(11):6183-9. (PMID: 9497340)
CNS Oncol. 2014 Mar;3(2):123-36. (PMID: 25055018)
Nat Rev Cancer. 2007 Oct;7(10):733-6. (PMID: 17882276)
J Biol Chem. 2009 Apr 24;284(17):11007-11. (PMID: 19091743)
Neuron. 2008 Jun 26;58(6):832-46. (PMID: 18579075)
Cell Oncol (Dordr). 2019 Feb;42(1):41-54. (PMID: 30209685)
J Biol Chem. 2008 Aug 22;283(34):23004-15. (PMID: 18577512)
Biochem J. 2017 Sep 7;474(18):3207-3226. (PMID: 28768733)
PLoS One. 2014 Jan 15;9(1):e86037. (PMID: 24454952)
Nat Rev Drug Discov. 2014 Feb;13(2):140-56. (PMID: 24481312)
Neuropsychiatr Dis Treat. 2018 Dec 24;15:83-94. (PMID: 30636874)

2018048 Open Project of State Key Laboratory of Medicinal Chemical Biology, Nankai University; 63191106 Fundamental Research Funds for the Central Universities, Nankai University; 81671380 Chinese National Natural Science Foundation; 81573737 Chinese National Natural Science Foundation; 17JCZDJC35900 Key Project of Tianjin National Natural Science Foundation; 172102310103 Science and Technology Development Foundation of Henan Province; 2018020480 Henan Provincial Medical Science and Technology Project; 81902477 National Natural Science Foundation of China

Keywords: BRAP; Cancer stem cells; Glioma; mTOR

0 (Proteins)
0 (Transforming Growth Factor beta)
EC 2.3.2.27 (BRAP protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)

Date Created: 20191129 Date Completed: 20201207 Latest Revision: 20211204

20240829

10.1007/s13402-019-00482-8

31776938