lncRNA PVT1 promotes hepatitis B virus‑positive liver cancer progression by disturbing histone methylation on the c‑Myc promoter

Jiang,Bei; Yang,Bing; Wang,Qin; Zheng,Xiaoya; Guo,Yu; Lu,Wei

doi:10.3892/or.2019.7444

lncRNA PVT1 promotes hepatitis B virus‑positive liver cancer progression by disturbing histone methylation on the c‑Myc promoter

Authors:
- Bei Jiang
- Bing Yang
- Qin Wang
- Xiaoya Zheng
- Yu Guo
- Wei Lu
View Affiliations

Affiliations: Tianjin Second People's Hospital, Tianjin 300192, P.R. China, Department of Cell Biology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, P.R. China, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, P.R. China, Department of Clinical Laboratory, Nankai Hospital, Tianjin 300100, P.R. China
Published online on: December 23, 2019 https://doi.org/10.3892/or.2019.7444
Pages: 718-726

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

Long noncoding RNA (LncRNA) PVT1 has recently been reported to be involved in the development of hepatocellular carcinoma (HCC). We aimed to elucidate the correlation of PVT1 with hepatitis B virus‑positive HCC in the clinic, and the roles of PVT1 in liver cancer cell biology, as well as to investigate the underlying molecular mechanisms. qPCR analysis was performed to examine the expression of PVT1 in hepatitis B virus‑positive HCC tissues and liver cancer cell lines. lncRNA PVT1 overexpression and knockdown were achieved by transfection of an overexpression vector or shRNA. Cell proliferation, colony formation, migration, apoptosis, and invasion capabilities were examined, accordingly. RNA pull‑down assay was employed to examine the connection between PVT1 and the PRC2 complex. Chromatin immunoprecipitation was employed to test the combination with EZH2 protein and H3K27me3 level on the MYC promoter. The results revealed that upregulation of PVT1 was detected in hepatitis B virus‑positive HCC tissues compared with that noted in the HBV‑negative samples. lncRNA PVT1 enhanced cell proliferation, migration, and invasion in the hepatitis B virus‑positive Hep3B cells rather than the hepatitis B virus‑negative HepG2 cells. PVT1 was able to bind EZH2 and obstruct the recruitment of EZH2 to the promoter of MYC therefore promoting MYC expression by altering H3K37me3 status in Hep3B liver cancer cells, and EZH2 protein was negatively correlated with lncRNA‑PVT1 expression. In conclusion, our results indicate that lncRNA PVT1 promotes hepatitis B virus‑positive liver cancer progression by disturbing histone methylation on the MYC promoter, suggesting that lncRNA PVT1 may be a potential target for developing diagnostic and therapeutic strategies of hepatitis B virus‑positive liver cancer at the early stages.

View Figures

View References

1	Ringelhan M, Pfister D, O'Connor T, Pikarsky E and Heikenwalder M: The immunology of hepatocellular carcinoma. Nat Immunol. 19:222–232. 2018. View Article : Google Scholar : PubMed/NCBI
2	Liu J, Yang HI, Lee MH, Lu SN, Jen CL, Batrla-Utermann R, Wang LY, You SL, Hsiao CK, Chen PJ, et al: Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma. Gut. 63:1648–1657. 2014. View Article : Google Scholar : PubMed/NCBI
3	Levrero M and Zucman-Rossi J: Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol. 64 (1 Suppl):S84–S101. 2016. View Article : Google Scholar : PubMed/NCBI
4	Shtivelman E, Henglein B, Groitl P, Lipp M and Bishop JM: Identification of a human transcription unit affected by the variant chromosomal translocations 2;8 and 8;22 of Burkitt lymphoma. Proc Natl Acad Sci USA. 86:3257–3260. 1989. View Article : Google Scholar : PubMed/NCBI
5	Huppi K, Siwarski D, Skurla R, Klinman D and Mushinski JF: Pvt-1 transcripts are found in normal tissues and are altered by reciprocal(6;15) translocations in mouse plasmacytomas. Proc Natl Acad Sci USA. 87:6964–698. 1990. View Article : Google Scholar : PubMed/NCBI
6	Barsotti AM, Beckerman R, Laptenko O, Huppi K, Caplen NJ and Prives C: p53-Dependent induction of PVT1 and miR-1204. J Biol Chem. 287:2509–2519. 2012. View Article : Google Scholar : PubMed/NCBI
7	Guan Y, Kuo WL, Stilwell JL, Takano H, Lapuk AV, Fridlyand J, Mao JH, Yu M, Miller MA, Santos JL, et al: Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clin Cancer Res. 13:5745–5755. 2007. View Article : Google Scholar : PubMed/NCBI
8	Takahashi Y, Sawada G, Kurashige J, Uchi R, Matsumura T, Ueo H, Takano Y, Eguchi H, Sudo T, Sugimachi K, et al: Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers. Br J Cancer. 110:164–171. 2014. View Article : Google Scholar : PubMed/NCBI
9	Ding J, Li D, Gong M, Wang J, Huang X, Wu T and Wang C: Expression and clinical significance of the long non-coding RNA PVT1 in human gastric cancer. OncoTargets Ther. 7:1625–1630. 2014. View Article : Google Scholar
10	Yang YR, Zang SZ, Zhong CL, Li YX, Zhao SS and Feng XJ: Increased expression of the lncRNA PVT1 promotes tumorigenesis in non-small cell lung cancer. Int J Clin Exp Pathol. 7:6929–6935. 2014.PubMed/NCBI
11	Xu Y, Luo X, He W, Chen G, Li Y, Li W, Wang X, Lai Y and Ye Y: Long non-coding RNA PVT1/miR-150/HIG2 axis regulates the proliferation, invasion and the balance of iron metabolism of hepatocellular carcinoma. Cell Physiol Biochem. 49:1403–1419. 2018. View Article : Google Scholar : PubMed/NCBI
12	Guo J, Hao C, Wang C and Li L: Long noncoding RNA PVT1 modulates hepatocellular carcinoma cell proliferation and apoptosis by recruiting EZH2. Cancer Cell Int. 18:982018. View Article : Google Scholar : PubMed/NCBI
13	Derderian C, Orunmuyi AT, Olapade-Olaopa EO and Ogunwobi OO: PVT1 signaling is a mediator of cancer progression. Front Oncol. 9:5022019. View Article : Google Scholar : PubMed/NCBI
14	Cui M, You L, Ren X, Zhao W, Liao Q and Zhao Y: Long non-coding RNA PVT1 and cancer. Biochem Biophys Res Commun. 471:10–4. 2016. View Article : Google Scholar : PubMed/NCBI
15	Chen L, Sun L, Dong L, Cui P, Xia Z, Li C and Zhu Y: The role of long noncoding RNA-LET in cell proliferation and invasion of nasopharyngeal carcinoma and its mechanism. OncoTargets Ther. 10:2769–2778. 2017. View Article : Google Scholar
16	Davidovich C and Cech TR: The recruitment of chromatin modifiers by long noncoding RNAs: Lessons from PRC2. RNA. 21:2007–2022. 2015. View Article : Google Scholar : PubMed/NCBI
17	Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, et al: Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA. 106:11667–116672. 2009. View Article : Google Scholar : PubMed/NCBI
18	He A, Shen X, Ma Q, Cao J, von Gise A, Zhou P, Wang G, Marquez VE, Orkin SH and Pu WT: PRC2 directly methylates GATA4 and represses its transcriptional activity. Genes Dev. 26:37–42. 2012. View Article : Google Scholar : PubMed/NCBI
19	Chen Y, Lin MC, Wang H, Chan CY, Jiang L, Ngai SM, Yu J, He ML, Shaw PC, Yew DT, et al: Proteomic analysis of EZH2 downstream target proteins in hepatocellular carcinoma. Proteomics. 7:3097–3104. 2007. View Article : Google Scholar : PubMed/NCBI
20	Villanueva A: Hepatocellular Carcinoma. N Engl J Med. 380:1450–1462. 2019. View Article : Google Scholar : PubMed/NCBI
21	Pfeiffer E, Kegel V, Zeilinger K, Hengstler JG, Nüssler AK, Seehofer D and Damm G: Featured article: Isolation, characterization, and cultivation of human hepatocytes and non-parenchymal liver cells. Exp Biol Med (Maywood). 240:645–656. 2015. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Colombo T, Farina L, Macino G and Paci P: PVT1: A rising star among oncogenic long noncoding RNAs. Biomed Res Int. 2015:3042082015. View Article : Google Scholar : PubMed/NCBI
24	Xu MD, Wang Y, Weng W, Wei P, Qi P, Zhang Q, Tan C, Ni SJ, Dong L, Yang Y, et al: A positive feedback loop of lncRNA-PVT1 and FOXM1 facilitates gastric cancer growth and invasion. Clin Cancer Res. 23:2071–2080. 2017. View Article : Google Scholar : PubMed/NCBI
25	Zhang XW, Bu P, Liu L, Zhang XZ and Li J: Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance. Biochem Biophys Res Commun. 462:227–232. 2015. View Article : Google Scholar : PubMed/NCBI
26	Ezhkova E, Pasolli HA, Parker JS, Stokes N, Su IH, Hannon G, Tarakhovsky A and Fuchs E: Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 136:1122–1135. 2009. View Article : Google Scholar : PubMed/NCBI
27	Gao SB, Zheng QF, Xu B, Pan CB, Li KL, Zhao Y, Zheng QL, Lin X, Xue LX and Jin GH: EZH2 represses target genes through H3K27-dependent and H3K27-independent mechanisms in hepatocellular carcinoma. Mol Cancer Res. 12:1388–1397. 2014. View Article : Google Scholar : PubMed/NCBI
28	Kong R, Zhang EB, Yin DD, You LH, Xu TP, Chen WM, Xia R, Wan L, Sun M, Wang ZX, et al: Long noncoding RNA PVT1 indicates a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically regulating p15 and p16. Mol Cancer. 14:822015. View Article : Google Scholar : PubMed/NCBI
29	Zhang S, Zhang G and Liu J: Long noncoding RNA PVT1 promotes cervical cancer progression through epigenetically silencing miR-200b. APMIS. 124:649–658. 2016. View Article : Google Scholar : PubMed/NCBI
30	Wan L, Sun M, Liu GJ, Wei CC, Zhang EB, Kong R, Xu TP, Huang MD and Wang ZX: Long noncoding RNA PVT1 promotes non-small cell lung cancer cell proliferation through epigenetically regulating LATS2 expression. Mol Cancer Ther. 15:1082–1094. 2016. View Article : Google Scholar : PubMed/NCBI
31	Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, Ronning P, Reuland B, Guenther K, Beadnell TC, et al: PVT1 dependence in cancer with MYC copy-number increase. Nature. 512:82–86. 2014. View Article : Google Scholar : PubMed/NCBI
32	Clark DN and Hu J: Hepatitis B virus reverse transcriptase-target of current antiviral therapy and future drug development. Antiviral Res. 123:132–137. 2015. View Article : Google Scholar : PubMed/NCBI