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Published in: Journal of Translational Medicine 1/2021

Open Access 01-12-2021 | Breast Cancer | Research

Long non-coding RNA ROR recruits histone transmethylase MLL1 to up-regulate TIMP3 expression and promote breast cancer progression

Authors: Aixia Hu, Fan Hong, Daohong Li, Yuwei Jin, Lingfei Kon, Ziguang Xu, Hui He, Qi Xie

Published in: Journal of Translational Medicine | Issue 1/2021

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Abstract

Background

As a significant cause of cancer deaths worldwide, breast cancer continues to be a troublesome malignancy. Long non-coding RNAs (lncRNAs) have been implicated in the development of breast cancer. Abnormal methylation has been associated with unfavorable breast cancer prognosis. Herein, the current study aimed to elucidate the role of lncRNA ROR in breast cancer.

Methods

RT-qPCR was performed to determine whether lncRNA ROR was highly expressed in breast cancer tissues, while lncRNA ROR expression was detected in both the nuclear and cytoplasm of breast cancer cells. MCF-7 cells were subsequently introduced with oe-lncRNA ROR, sh-lncRNA ROR to explore the effects of lncRNA ROR on cell proliferation, invasion and apoptosis.

Results

RIP, RNA pull-down and ChIP assays provided evidence suggesting that lncRNA ROR recruited transmethylase MLL1 to promote H3K4 trimethylation that enhanced TIMP3 transcription. The rescue experiments demonstrated that lncRNA ROR knockdown could inhibit the progression of breast cancer via the downregulation of TIMP3. Finally, the in vivo experiment findings consistently highlighted the suppressive effects of lncRNA ROR silencing on tumor growth.

Conclusion

Taken together, our study demonstrates that silencing of lncRNA ROR inhibits breast cancer progression via repression of transmethylase MLL1 and TIMP3, emphasizing the potential of lncRNA ROR as a novel target against breast cancer.
Literature
2.
go back to reference Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.PubMedCrossRef Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.PubMedCrossRef
3.
go back to reference Carreira H, Williams R, Müller M, Harewood R, Stanway S, Bhaskaran K. Associations between breast cancer survivorship and adverse mental health outcomes: a systematic review. J Natl Cancer Inst. 2018;110(12):1311–27.PubMedPubMedCentralCrossRef Carreira H, Williams R, Müller M, Harewood R, Stanway S, Bhaskaran K. Associations between breast cancer survivorship and adverse mental health outcomes: a systematic review. J Natl Cancer Inst. 2018;110(12):1311–27.PubMedPubMedCentralCrossRef
4.
go back to reference Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, et al. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. CA Cancer J Clin. 2016;66(1):43–73.PubMedCrossRef Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, et al. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. CA Cancer J Clin. 2016;66(1):43–73.PubMedCrossRef
5.
go back to reference Asiago VM, Alvarado LZ, Shanaiah N, Gowda GA, Owusu-Sarfo K, Ballas RA, et al. Early detection of recurrent breast cancer using metabolite profiling. Cancer Res. 2010;70(21):8309–18.PubMedPubMedCentralCrossRef Asiago VM, Alvarado LZ, Shanaiah N, Gowda GA, Owusu-Sarfo K, Ballas RA, et al. Early detection of recurrent breast cancer using metabolite profiling. Cancer Res. 2010;70(21):8309–18.PubMedPubMedCentralCrossRef
6.
go back to reference Visvanathan K, Fackler MS, Zhang Z, Lopez-Bujanda ZA, Jeter SC, Sokoll LJ, et al. Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 prospective Biomarker study. J Clin Oncol. 2017;35(7):751–8.PubMedCrossRef Visvanathan K, Fackler MS, Zhang Z, Lopez-Bujanda ZA, Jeter SC, Sokoll LJ, et al. Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 prospective Biomarker study. J Clin Oncol. 2017;35(7):751–8.PubMedCrossRef
7.
go back to reference Ye N, Wang B, Quan ZF, Cao SJ, Wen XT, Huang Y, et al. Functional roles of long non-coding RNA in human breast cancer. Asian Pac J Cancer Prev. 2014;15(15):5993–7.PubMedCrossRef Ye N, Wang B, Quan ZF, Cao SJ, Wen XT, Huang Y, et al. Functional roles of long non-coding RNA in human breast cancer. Asian Pac J Cancer Prev. 2014;15(15):5993–7.PubMedCrossRef
8.
go back to reference Ulitsky I. Evolution to the rescue: using comparative genomics to understand long non-coding RNAs. Nat Rev Genet. 2016;17(10):601–14.PubMedCrossRef Ulitsky I. Evolution to the rescue: using comparative genomics to understand long non-coding RNAs. Nat Rev Genet. 2016;17(10):601–14.PubMedCrossRef
10.
go back to reference Li L, Gu M, You B, Shi S, Shan Y, Bao L, et al. Long non-coding RNA ROR promotes proliferation, migration and chemoresistance of nasopharyngeal carcinoma. Cancer Sci. 2016;107(9):1215–22.PubMedPubMedCentralCrossRef Li L, Gu M, You B, Shi S, Shan Y, Bao L, et al. Long non-coding RNA ROR promotes proliferation, migration and chemoresistance of nasopharyngeal carcinoma. Cancer Sci. 2016;107(9):1215–22.PubMedPubMedCentralCrossRef
11.
go back to reference Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214(8):2387–404.PubMedPubMedCentralCrossRef Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214(8):2387–404.PubMedPubMedCentralCrossRef
12.
go back to reference Fan J, Xing Y, Wen X, Jia R, Ni H, He J, et al. Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol. 2015;16:139.PubMedPubMedCentralCrossRef Fan J, Xing Y, Wen X, Jia R, Ni H, He J, et al. Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol. 2015;16:139.PubMedPubMedCentralCrossRef
13.
14.
go back to reference Rabello Ddo A, de Moura CA, de Andrade RV, Motoyama AB, Silva FP. Altered expression of MLL methyltransferase family genes in breast cancer. Int J Oncol. 2013;43(2):653–60.PubMedCrossRef Rabello Ddo A, de Moura CA, de Andrade RV, Motoyama AB, Silva FP. Altered expression of MLL methyltransferase family genes in breast cancer. Int J Oncol. 2013;43(2):653–60.PubMedCrossRef
15.
go back to reference Shao Q, Ning H, Lv J, Liu Y, Zhao X, Ren G, et al. Regulation of Th1/Th2 polarization by tissue inhibitor of metalloproteinase-3 via modulating dendritic cells. Blood. 2012;119(20):4636–44.PubMedCrossRef Shao Q, Ning H, Lv J, Liu Y, Zhao X, Ren G, et al. Regulation of Th1/Th2 polarization by tissue inhibitor of metalloproteinase-3 via modulating dendritic cells. Blood. 2012;119(20):4636–44.PubMedCrossRef
16.
go back to reference Maleva Kostovska I, Jakimovska M, Popovska-Jankovic K, Kubelka-Sabit K, Karagjozov M, Plaseska-Karanfilska D. TIMP3 promoter methylation represents an epigenetic marker of BRCA1ness breast cancer tumours. Pathol Oncol Res. 2018;24(4):937–40.PubMedCrossRef Maleva Kostovska I, Jakimovska M, Popovska-Jankovic K, Kubelka-Sabit K, Karagjozov M, Plaseska-Karanfilska D. TIMP3 promoter methylation represents an epigenetic marker of BRCA1ness breast cancer tumours. Pathol Oncol Res. 2018;24(4):937–40.PubMedCrossRef
17.
go back to reference Alspach E, Stewart SA. RNA-binding protein immunoprecipitation (RIP) to examine AUF1 binding to senescence-associated secretory phenotype (SASP) factor mRNA. Bio Protoc. 2015;5(10):e1481.PubMed Alspach E, Stewart SA. RNA-binding protein immunoprecipitation (RIP) to examine AUF1 binding to senescence-associated secretory phenotype (SASP) factor mRNA. Bio Protoc. 2015;5(10):e1481.PubMed
19.
go back to reference Xu J, Lu MX, Cui YD, Du YZ. Selection and evaluation of reference genes for expression analysis using qRT-PCR in Chilo suppressalis (Lepidoptera: Pyralidae). J Econ Entomol. 2017;110(2):683–91.PubMed Xu J, Lu MX, Cui YD, Du YZ. Selection and evaluation of reference genes for expression analysis using qRT-PCR in Chilo suppressalis (Lepidoptera: Pyralidae). J Econ Entomol. 2017;110(2):683–91.PubMed
20.
go back to reference Fan J, Xing Y, Wen X, Jia R, Ni H, He J, et al. Erratum to: Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol. 2015;16:275.PubMedPubMedCentralCrossRef Fan J, Xing Y, Wen X, Jia R, Ni H, He J, et al. Erratum to: Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol. 2015;16:275.PubMedPubMedCentralCrossRef
21.
go back to reference Li J, Yu B, Deng P, Cheng Y, Yu Y, Kevork K, et al. KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/beta-catenin signalling. Nat Commun. 2017;8:15146.PubMedPubMedCentralCrossRef Li J, Yu B, Deng P, Cheng Y, Yu Y, Kevork K, et al. KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/beta-catenin signalling. Nat Commun. 2017;8:15146.PubMedPubMedCentralCrossRef
22.
go back to reference Jackson HW, Hojilla CV, Weiss A, Sanchez OH, Wood GA, Khokha R. Timp3 deficient mice show resistance to developing breast cancer. PLoS ONE. 2015;10(3):e0120107.PubMedPubMedCentralCrossRef Jackson HW, Hojilla CV, Weiss A, Sanchez OH, Wood GA, Khokha R. Timp3 deficient mice show resistance to developing breast cancer. PLoS ONE. 2015;10(3):e0120107.PubMedPubMedCentralCrossRef
24.
25.
go back to reference Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.CrossRef Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.CrossRef
26.
go back to reference Qu CH, Sun QY, Zhang FM, Jia YM. Long non-coding RNA ROR is a novel prognosis factor associated with non-small-cell lung cancer progression. Eur Rev Med Pharmacol Sci. 2017;21(18):4087–91.PubMed Qu CH, Sun QY, Zhang FM, Jia YM. Long non-coding RNA ROR is a novel prognosis factor associated with non-small-cell lung cancer progression. Eur Rev Med Pharmacol Sci. 2017;21(18):4087–91.PubMed
27.
go back to reference Li Y, Jiang B, Zhu H, Qu X, Zhao L, Tan Y, et al. Inhibition of long non-coding RNA ROR reverses resistance to Tamoxifen by inducing autophagy in breast cancer. Tumour Biol. 2017;39(6):1010428317705790.PubMed Li Y, Jiang B, Zhu H, Qu X, Zhao L, Tan Y, et al. Inhibition of long non-coding RNA ROR reverses resistance to Tamoxifen by inducing autophagy in breast cancer. Tumour Biol. 2017;39(6):1010428317705790.PubMed
28.
go back to reference Renault TT, Dejean LM, Manon S. A brewing understanding of the regulation of Bax function by Bcl-xL and Bcl-2. Mech Ageing Dev. 2017;161(Pt B):201–10.PubMedCrossRef Renault TT, Dejean LM, Manon S. A brewing understanding of the regulation of Bax function by Bcl-xL and Bcl-2. Mech Ageing Dev. 2017;161(Pt B):201–10.PubMedCrossRef
29.
go back to reference Ebrahim AS, Sabbagh H, Liddane A, Raufi A, Kandouz M, Al-Katib A. Hematologic malignancies: newer strategies to counter the BCL-2 protein. J Cancer Res Clin Oncol. 2016;142(9):2013–22.PubMedCrossRef Ebrahim AS, Sabbagh H, Liddane A, Raufi A, Kandouz M, Al-Katib A. Hematologic malignancies: newer strategies to counter the BCL-2 protein. J Cancer Res Clin Oncol. 2016;142(9):2013–22.PubMedCrossRef
30.
go back to reference Westphal D, Dewson G, Czabotar PE, Kluck RM. Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta. 2011;1813(4):521–31.PubMedCrossRef Westphal D, Dewson G, Czabotar PE, Kluck RM. Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta. 2011;1813(4):521–31.PubMedCrossRef
31.
go back to reference Mailand N, Gibbs-Seymour I, Bekker-Jensen S. Regulation of PCNA-protein interactions for genome stability. Nat Rev Mol Cell Biol. 2013;14(5):269–82.PubMedCrossRef Mailand N, Gibbs-Seymour I, Bekker-Jensen S. Regulation of PCNA-protein interactions for genome stability. Nat Rev Mol Cell Biol. 2013;14(5):269–82.PubMedCrossRef
32.
go back to reference Tanei T, Shimomura A, Shimazu K, Nakayama T, Kim SJ, Iwamoto T, et al. Prognostic significance of Ki67 index after neoadjuvant chemotherapy in breast cancer. Eur J Surg Oncol. 2011;37(2):155–61.PubMedCrossRef Tanei T, Shimomura A, Shimazu K, Nakayama T, Kim SJ, Iwamoto T, et al. Prognostic significance of Ki67 index after neoadjuvant chemotherapy in breast cancer. Eur J Surg Oncol. 2011;37(2):155–61.PubMedCrossRef
33.
go back to reference Vandenbroucke RE, Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov. 2014;13(12):904–27.PubMedCrossRef Vandenbroucke RE, Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov. 2014;13(12):904–27.PubMedCrossRef
35.
go back to reference Luo Y, Yu T, Zhang Q, Fu Q, Hu Y, Xiang M, et al. Upregulated N-cadherin expression is associated with poor prognosis in epithelial-derived solid tumours: a meta-analysis. Eur J Clin Invest. 2018;48(4):e12903.PubMedCentralCrossRef Luo Y, Yu T, Zhang Q, Fu Q, Hu Y, Xiang M, et al. Upregulated N-cadherin expression is associated with poor prognosis in epithelial-derived solid tumours: a meta-analysis. Eur J Clin Invest. 2018;48(4):e12903.PubMedCentralCrossRef
36.
go back to reference Hu QP, Kuang JY, Yang QK, Bian XW, Yu SC. Beyond a tumor suppressor: soluble E-cadherin promotes the progression of cancer. Int J Cancer. 2016;138(12):2804–12.PubMedCrossRef Hu QP, Kuang JY, Yang QK, Bian XW, Yu SC. Beyond a tumor suppressor: soluble E-cadherin promotes the progression of cancer. Int J Cancer. 2016;138(12):2804–12.PubMedCrossRef
37.
go back to reference Hu Q, Peng J, Liu W, He X, Cui L, Chen X, et al. Elevated cleaved caspase-3 is associated with shortened overall survival in several cancer types. Int J Clin Exp Pathol. 2014;7(8):5057–70.PubMedPubMedCentral Hu Q, Peng J, Liu W, He X, Cui L, Chen X, et al. Elevated cleaved caspase-3 is associated with shortened overall survival in several cancer types. Int J Clin Exp Pathol. 2014;7(8):5057–70.PubMedPubMedCentral
38.
go back to reference Zhang HY, Liang F, Zhang JW, Wang F, Wang L, Kang XG. Effects of long noncoding RNA-ROR on tamoxifen resistance of breast cancer cells by regulating microRNA-205. Cancer Chemother Pharmacol. 2017;79(2):327–37.PubMedCrossRef Zhang HY, Liang F, Zhang JW, Wang F, Wang L, Kang XG. Effects of long noncoding RNA-ROR on tamoxifen resistance of breast cancer cells by regulating microRNA-205. Cancer Chemother Pharmacol. 2017;79(2):327–37.PubMedCrossRef
39.
go back to reference Wang S, Liu F, Deng J, Cai X, Han J, Liu Q. Long noncoding RNA ROR Regulates proliferation, invasion, and stemness of gastric cancer stem cell. Cell Reprogram. 2016;18(5):319–26.PubMedCrossRef Wang S, Liu F, Deng J, Cai X, Han J, Liu Q. Long noncoding RNA ROR Regulates proliferation, invasion, and stemness of gastric cancer stem cell. Cell Reprogram. 2016;18(5):319–26.PubMedCrossRef
40.
go back to reference Han XG, Li Y, Mo HM, Li K, Lin D, Zhao CQ, et al. TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances. Tumour Biol. 2016;37(7):8857–67.PubMedCrossRef Han XG, Li Y, Mo HM, Li K, Lin D, Zhao CQ, et al. TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances. Tumour Biol. 2016;37(7):8857–67.PubMedCrossRef
41.
go back to reference Alicea-Velazquez NL, Shinsky SA, Loh DM, Lee JH, Skalnik DG, Cosgrove MS. Targeted disruption of the interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 family proteins specifically inhibits MLL1 and SETd1A methyltransferase complexes. J Biol Chem. 2016;291(43):22357–72.PubMedPubMedCentralCrossRef Alicea-Velazquez NL, Shinsky SA, Loh DM, Lee JH, Skalnik DG, Cosgrove MS. Targeted disruption of the interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 family proteins specifically inhibits MLL1 and SETd1A methyltransferase complexes. J Biol Chem. 2016;291(43):22357–72.PubMedPubMedCentralCrossRef
42.
go back to reference Wang XX, Fu L, Li X, Wu X, Zhu Z, Fu L, et al. Somatic mutations of the mixed-lineage leukemia 3 (MLL3) gene in primary breast cancers. Pathol Oncol Res. 2011;17(2):429–33.PubMedCrossRef Wang XX, Fu L, Li X, Wu X, Zhu Z, Fu L, et al. Somatic mutations of the mixed-lineage leukemia 3 (MLL3) gene in primary breast cancers. Pathol Oncol Res. 2011;17(2):429–33.PubMedCrossRef
43.
go back to reference Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, et al. Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol Cell Biol. 2009;29(22):6074–85.PubMedPubMedCentralCrossRef Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, et al. Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol Cell Biol. 2009;29(22):6074–85.PubMedPubMedCentralCrossRef
44.
go back to reference Hoque MO, Begum S, Brait M, Jeronimo C, Zahurak M, Ostrow KL, et al. Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer. J Urol. 2008;179(2):743–7.PubMedCrossRef Hoque MO, Begum S, Brait M, Jeronimo C, Zahurak M, Ostrow KL, et al. Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer. J Urol. 2008;179(2):743–7.PubMedCrossRef
45.
go back to reference Lui EL, Loo WT, Zhu L, Cheung MN, Chow LW. DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma. Biomed Pharmacother. 2005;59(Suppl 2):S363-5.PubMedCrossRef Lui EL, Loo WT, Zhu L, Cheung MN, Chow LW. DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma. Biomed Pharmacother. 2005;59(Suppl 2):S363-5.PubMedCrossRef
Metadata
Title
Long non-coding RNA ROR recruits histone transmethylase MLL1 to up-regulate TIMP3 expression and promote breast cancer progression
Authors
Aixia Hu
Fan Hong
Daohong Li
Yuwei Jin
Lingfei Kon
Ziguang Xu
Hui He
Qi Xie
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-020-02682-5

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