Abstract
Breast cancer, a multifactorial disease, represents one of the leading causes of cancer-related morbidity and mortality in women. This study set out to elucidate the underlying mechanism by which lncRNA UCA1 affects the m6A modification of miR-375 by mediating the DNA methylation of METTL14 and then altering SOX12 expression in breast cancer. First, the expression patterns of lncRNA UCA1, miR-375, and apoptosis-related factors were quantitated by means of RT-qPCR and western blot analysis. In addition, the proliferation, invasion, and apoptosis of cells were detected using CCK-8, Transwell, and flow cytometry, respectively. RIP was performed to further uncover the interaction of lncRNA UCA1 and DNA methyltransferases, and MSP was employed for METTL14 promoter region methylation. The DNA methyltransferase enrichment in the METTL14 promoter region was measured by ChIP. The targeting relationship between miR-375 and SOX12 was confirmed by bioinformatics analysis and dual-luciferase report assay. Lastly, the aforementioned mechanism was also verified using tumor xenograft in vivo. It was found the elevated lncRNA UCA1 expression levels serve as a risk factor of poor prognosis in breast cancer. Meanwhile, silencing lncRNA UCA1 could inhibit the proliferation and invasion, but promote apoptosis of breast cancer cells by reducing the DNA methylation of METTL14 and augmenting its expression. Furthermore, METTL14 was observed to mediate the low miR-375 expression through m6A modification, leading to increased SOX12 expression levels in breast cancer. Altogether, findings obtained in our study indicated that silencing lncRNA UCA1 curbed the progression of breast cancer through the METTL14-miR-375-SOX12 axis.
Similar content being viewed by others
References
Hwang SY, Park S, Kwon Y. Recent therapeutic trends and promising targets in triple negative breast cancer. Pharm Ther. 2019;199:30–57.
Liu X, Song J, Kang Y, Wang Y, Chen A. Long noncoding RNA SOX21-AS1 regulates the progression of triple-negative breast cancer through regulation of miR-520a-5p/ORMDL3 axis. J Cell Biochem. 2020. https://doi.org/10.1002/jcb.29674.
Hua K, Deng X, Hu J, Ji C, Yu Y, Li J, et al. Long noncoding RNA HOST2, working as a competitive endogenous RNA, promotes STAT3-mediated cell proliferation and migration via decoying of let-7b in triple-negative breast cancer. J Exp Clin Cancer Res. 2020;39:58.
Duan Q, Xu M, Wu M, Zhang X, Gan M, Jiang H. Long noncoding RNA UCA1 promotes cell growth, migration, and invasion by targeting miR-143-3p in oral squamous cell carcinoma. Cancer Med. 2020;9:3115–29.
Gao H, Yang JY, Tong LX, Jin H, Liu CZ. Long noncoding RNA UCA1 promotes proliferation and metastasis of thyroid cancer cells by sponging miR-497-3p. Eur Rev Med Pharm Sci. 2020;24:728–34.
Nasrollahzadeh-Khakiani M, Emadi-Baygi M, Nikpour P. Augmented expression levels of lncRNAs ecCEBPA and UCA1 in gastric cancer tissues and their clinical significance. Iran J Basic Med Sci. 2017;20:1149–58.
Lan Q, Liu PY, Haase J, Bell JL, Huttelmaier S, Liu T. The critical role of RNA m(6)A methylation in cancer. Cancer Res. 2019;79:1285–92.
Yi D, Wang R, Shi X, Xu L, Yilihamu Y, Sang J. METTL14 promotes the migration and invasion of breast cancer cells by modulating N6methyladenosine and hsamiR146a5p expression. Oncol Rep. 2020;43:1375–86.
Chen X, Xu M, Xu X, Zeng K, Liu X, Sun L, et al. METTL14 suppresses CRC progression via regulating N6-methyladenosine-dependent primary miR-375 processing. Mol Ther. 2020;28:599–612.
Zou Q, Yi W, Huang J, Fu F, Chen G, Zhong D. MicroRNA-375 targets PAX6 and inhibits the viability, migration and invasion of human breast cancer MCF-7 cells. Exp Ther Med. 2017;14:1198–204.
Tang H, Huang X, Wang J, Yang L, Kong Y, Gao G, et al. circKIF4A acts as a prognostic factor and mediator to regulate the progression of triple-negative breast cancer. Mol Cancer. 2019;18:23.
Ding H, Quan H, Yan W, Han J. Silencing of SOX12 by shRNA suppresses migration, invasion and proliferation of breast cancer cells. Biosci Rep. 2016;36:e00389.
Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol. 1999;17:1974–82.
Yao F, Wang Q, Wu Q. The prognostic value and mechanisms of lncRNA UCA1 in human cancer. Cancer Manag Res. 2019;11:7685–96.
Li Z, Yu D, Li H, Lv Y, Li S. Long noncoding RNA UCA1 confers tamoxifen resistance in breast cancer endocrinotherapy through regulation of the EZH2/p21 axis and the PI3K/AKT signaling pathway. Int J Oncol. 2019;54:1033–42.
Wu L, Wu D, Ning J, Liu W, Zhang D. Changes of N6-methyladenosine modulators promote breast cancer progression. BMC Cancer. 2019;19:326.
Nazari SS, Mukherjee P. An overview of mammographic density and its association with breast cancer. Breast Cancer. 2018;25:259–67.
Shi W, Tang T, Li X, Deng S, Li R, Wang Y, et al. Methylation-mediated silencing of miR-133a-3p promotes breast cancer cell migration and stemness via miR-133a-3p/MAML1/DNMT3A positive feedback loop. J Exp Clin Cancer Res. 2019;38:429.
Cao Y, Xiong JB, Zhang GY, Liu Y, Jie ZG, Li ZR. Long noncoding RNA UCA1 regulates PRL-3 expression by sponging microRNA-495 to promote the progression of gastric cancer. Mol Ther Nucleic Acids. 2020;19:853–64.
Yang TJ, Wang L, Zhang Y, Zheng JD, Liu L. LncRNA UCA1 regulates cervical cancer survival and EMT occurrence by targeting miR-155. Eur Rev Med Pharm Sci. 2020;24:9869–79.
Sun T, Wu Z, Wang X, Wang Y, Hu X, Qin W, et al. LNC942 promoting METTL14-mediated m(6)A methylation in breast cancer cell proliferation and progression. Oncogene 2020;39:5358–72.
Yang X, Zhang S, He C, Xue P, Zhang L, He Z, et al. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol Cancer. 2020;19:46.
Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N(6) -methyladenosine-dependent primary MicroRNA processing. Hepatology. 2017;65:529–43.
Li L, Zhang T, Chen Y, Song J, Meng Y, Liu S, et al. [Expression of transcription factor SOX12 in lung adenocarcinoma and its clinical significance]. Nan Fang Yi Ke Da Xue Xue Bao. 2019;39:186–91.
Du Y, Shen L, Zhang W, Ding R, Li Q, Li S, et al. Functional analyses of microRNA-326 in breast cancer development. Biosci Rep. 2019;39:BSR20190787.
Du F, Feng W, Chen S, Wu S, Cao T, Yuan T, et al. Sex determining region Y-box 12 (SOX12) promotes gastric cancer metastasis by upregulating MMP7 and IGF1. Cancer Lett. 2019;452:103–18.
Zhao XB, Ji FY, Li HR, Zhu HH, Zhao ZZ, Ling J, et al. P22077 inhibits LPS-induced inflammatory response by promoting K48-linked ubiquitination and degradation of TRAF6. Aging (Albany NY). 2020;12:10969–82.
Liu J, Luo C, Zhang C, Cai Q, Lin J, Zhu T, et al. Upregulated lncRNA UCA1 inhibits trophoblast cell invasion and proliferation by downregulating JAK2. J Cell Physiol. 2020. https://doi.org/10.1002/jcp.29643.
Acknowledgements
The authors thank the reviewers for their helpful comments.
Funding
This work is supported by the Youth Fund of the First Hospital of Lanzhou University (ldyyyn2019-85).
Author information
Authors and Affiliations
Contributions
CPZ designed the study. XLL, YXX, and BXY collated the data, carried out data analyses, and produced the initial draft of the manuscript. QLG contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Zhao, C., Ling, X., Xia, Y. et al. LncRNA UCA1 promotes SOX12 expression in breast cancer by regulating m6A modification of miR-375 by METTL14 through DNA methylation. Cancer Gene Ther 29, 1043–1055 (2022). https://doi.org/10.1038/s41417-021-00390-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41417-021-00390-w
- Springer Nature America, Inc.
This article is cited by
-
LncRNA RASAL2-AS1 promotes METTL14-mediated m6A methylation in the proliferation and progression of head and neck squamous cell carcinoma
Cancer Cell International (2024)
-
Role of ferroptosis and ferroptosis-related long non'coding RNA in breast cancer
Cellular & Molecular Biology Letters (2024)
-
Emerging role of RNA modification and long noncoding RNA interaction in cancer
Cancer Gene Therapy (2024)
-
Small RNA modifications: regulatory molecules and potential applications
Journal of Hematology & Oncology (2023)
-
Methyltransferase-like proteins in cancer biology and potential therapeutic targeting
Journal of Hematology & Oncology (2023)