RREB1-induced Upregulation of the LncRNA AGAP2-AS1 Regulates the Proliferation and Migration of Pancreatic Cancer Partly Through Suppressing ANKRD1 and ANGPTL4

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2019 Mar 1

PMID 30814490

Citations 67

Authors

Bingqing Hui

Hao Ji

Yetao Xu

Juan Wang

Zhonghua Ma

Chongguo Zhang

Keming Wang

Yan Zhou

Affiliations

Soon will be listed here.

Abstract

Long noncoding RNAs (lncRNAs) have been reported to be involved in a variety of human diseases, including cancers. However, their mechanisms have not yet been fully elucidated. We investigated lncRNA changes that may be associated with pancreatic cancer (PC) by analyzing published microarray data, and identified AGAP2-AS1 as a relatively overexpressed lncRNA in PC tissues. qRT-PCR assays were performed to examine expression levels of AGAP2-AS1. MTT assays, colony formation assays, and EdU assays were used to determine the proliferative capacity of cells. Flow cytometry and TUNEL assays were used to study the regulation of AGAP2-AS1 in the cell cycle and apoptosis. Transwell experiments were used to study changes in cell invasion and metastasis, and a nude mouse model was established to assess the effects of AGAP2-AS1 on tumorigenesis in vivo. RNA sequencing was performed to probe AGAP2-AS1-related pathways. Subcellular fractionation and FISH assays were used to determine the distribution of AGAP2-AS1 in PC cells, and RIP and ChIP were used to determine the molecular mechanism of AGAP2-AS1-mediated regulation of potential target genes. Increased expression of AGAP2-AS1 was associated with tumor size and pathological stage progression in patients with PC. RREB1 was found to activate transcription of AGAP2-AS1 in PC cells. AGAP2-AS1 affected proliferation, apoptosis, cycle arrest, invasion, and metastasis of PC cells in vitro, and AGAP2-AS1 regulated PC proliferation in vivo. Furthermore, AGAP2-AS1 epigenetically inhibited the expression of ANKRD1 and ANGPTL4 by recruiting zeste homolog 2 (EZH2), thereby promoting PC proliferation and metastasis. In summary, our data show that RREB1-induced upregulation of AGAP2-AS1 regulates cell proliferation and migration in PC partly through suppressing ANKRD1 and ANGPTL4 by recruiting EZH2. AGAP2-AS1 represents a potential target for the diagnosis and treatment of PC in the future.

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References

Ferre F, Colantoni A, Helmer-Citterich M . Revealing protein-lncRNA interaction. Brief Bioinform. 2015; 17(1):106-16. PMC: 4719072. DOI: 10.1093/bib/bbv031. View

Ulitsky I, Bartel D . lincRNAs: genomics, evolution, and mechanisms. Cell. 2013; 154(1):26-46. PMC: 3924787. DOI: 10.1016/j.cell.2013.06.020. View

Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P . Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002; 298(5595):1039-43. DOI: 10.1126/science.1076997. View

Zhang L, Sanagapalli S, Stoita A . Challenges in diagnosis of pancreatic cancer. World J Gastroenterol. 2018; 24(19):2047-2060. PMC: 5960811. DOI: 10.3748/wjg.v24.i19.2047. View

Siegel R, Miller K, Jemal A . Cancer statistics, 2018. CA Cancer J Clin. 2018; 68(1):7-30. DOI: 10.3322/caac.21442. View

Qi F, Liu X, Wu H, Yu X, Wei C, Huang X . Long noncoding AGAP2-AS1 is activated by SP1 and promotes cell proliferation and invasion in gastric cancer. J Hematol Oncol. 2017; 10(1):48. PMC: 5314629. DOI: 10.1186/s13045-017-0420-4. View

Fanale D, Castiglia M, Bazan V, Russo A . Involvement of Non-coding RNAs in Chemo- and Radioresistance of Colorectal Cancer. Adv Exp Med Biol. 2016; 937:207-28. DOI: 10.1007/978-3-319-42059-2_11. View

Li W, Sun M, Zang C, Ma P, He J, Zhang M . Upregulated long non-coding RNA AGAP2-AS1 represses LATS2 and KLF2 expression through interacting with EZH2 and LSD1 in non-small-cell lung cancer cells. Cell Death Dis. 2016; 7:e2225. PMC: 4917662. DOI: 10.1038/cddis.2016.126. View

Peng Z, Zhang C, Duan C . Functions and mechanisms of long noncoding RNAs in lung cancer. Onco Targets Ther. 2016; 9:4411-24. PMC: 4959596. DOI: 10.2147/OTT.S109549. View

10.

Khanduja J, Calvo I, Joh R, Hill I, Motamedi M . Nuclear Noncoding RNAs and Genome Stability. Mol Cell. 2016; 63(1):7-20. PMC: 5136474. DOI: 10.1016/j.molcel.2016.06.011. View

11.

Galaup A, Cazes A, le Jan S, Philippe J, Connault E, Le Coz E . Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. Proc Natl Acad Sci U S A. 2006; 103(49):18721-6. PMC: 1693729. DOI: 10.1073/pnas.0609025103. View

12.

Chang C, Hung M . The role of EZH2 in tumour progression. Br J Cancer. 2011; 106(2):243-7. PMC: 3261672. DOI: 10.1038/bjc.2011.551. View

13.

Hsieh H, Jou Y, Tung C, Tsai Y, Wang Y, Chi C . Epigenetic silencing of the dual-role signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment. Oncogene. 2017; 37(5):673-686. DOI: 10.1038/onc.2017.375. View

14.

Siegfried A, Romary C, Escudie F, Nicaise Y, Grand D, Rochaix P . RREB1-MKL2 fusion in biphenotypic "oropharyngeal" sarcoma: New entity or part of the spectrum of biphenotypic sinonasal sarcomas?. Genes Chromosomes Cancer. 2017; 57(4):203-210. DOI: 10.1002/gcc.22521. View

15.

Fatica A, Bozzoni I . Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2013; 15(1):7-21. DOI: 10.1038/nrg3606. View

16.

Khalil A, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D . Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009; 106(28):11667-72. PMC: 2704857. DOI: 10.1073/pnas.0904715106. View

17.

Lee J . Epigenetic regulation by long noncoding RNAs. Science. 2012; 338(6113):1435-9. DOI: 10.1126/science.1231776. View

18.

Birney E, Stamatoyannopoulos J, Dutta A, Guigo R, Gingeras T, Margulies E . Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007; 447(7146):799-816. PMC: 2212820. DOI: 10.1038/nature05874. View

19.

Margueron R, Reinberg D . The Polycomb complex PRC2 and its mark in life. Nature. 2011; 469(7330):343-9. PMC: 3760771. DOI: 10.1038/nature09784. View

20.

Kent O, Fox-Talbot K, Halushka M . RREB1 repressed miR-143/145 modulates KRAS signaling through downregulation of multiple targets. Oncogene. 2012; 32(20):2576-85. PMC: 8177721. DOI: 10.1038/onc.2012.266. View