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Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Research Article

H3K27ac-activated LncRNA NUTM2A-AS1 Facilitates the Progression of Colorectal Cancer Cells via MicroRNA-126-5p/FAM3C Axis

In Press, (this is not the final "Version of Record"). Available online 09 February, 2024
Author(s): Haiguan Lin, Shidong Hu, Yuxuan Li, Songyan Li, Da Teng, Yan Yang, Boyan Liu and Xiaohui Du*
Published on: 09 February, 2024

DOI: 10.2174/0115680096277956240119065938

Abstract

Objective: Long non-coding RNAs (lncRNAs) are of great importance in the process of colorectal cancer (CRC) tumorigenesis and progression. However, the functions and underlying molecular mechanisms of the majority of lncRNAs in CRC still lack clarity.

Methods: A Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect lncRNA NUTM2A-AS1 expression in CRC cell lines. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to examine the biological functions of lncRNA NUTM2A-AS1 in the proliferation and apoptosis of CRC cells. RT-qPCR and western blot were implemented for the detection of cell proliferation-, apoptosis-related proteins, and FAM3C. Bioinformatics analysis and dual- luciferase reporter assays were utilized to identify the mutual regulatory mechanism of ceRNAs.

Results: lncRNA NUTM2A-AS1 notably elevated in CRC cell lines and the silencing of NUTM2A- AS1 declined proliferation and facilitated apoptosis. Mechanistically, NUTM2A-AS1 was transcriptionally activated by histone H3 on lysine 27 acetylation (H3K27ac) enriched at its promoter region, and NUTM2A-AS1 acted as a sponge for miR-126-5p, leading to the upregulation of FAM3C expression in CRC cell lines.

Conclusion : Our research proposed NUTM2A-AS1 as an oncogenic lncRNA that facilitates CRC malignancy by upregulating FAM3C expression, which might provide new insight and a promising therapeutic target for the diagnosis and treatment of CRC.

[1]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin., 2021, 71(1), 7-33.
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[2]
Dekker, E.; Tanis, P.J.; Vleugels, J.L.A.; Kasi, P.M.; Wallace, M.B. Colorectal cancer. Lancet, 2019, 394(10207), 1467-1480.
[http://dx.doi.org/10.1016/S0140-6736(19)32319-0] [PMID: 31631858]
[3]
Slack, F.J.; Chinnaiyan, A.M. The role of non-coding RNAs in oncology. Cell, 2019, 179(5), 1033-1055.
[http://dx.doi.org/10.1016/j.cell.2019.10.017] [PMID: 31730848]
[4]
Dragomir, M.P.; Kopetz, S.; Ajani, J.A.; Calin, G.A. Non-coding RNAs in GI cancers: From cancer hallmarks to clinical utility. Gut, 2020, 69(4), 748-763.
[http://dx.doi.org/10.1136/gutjnl-2019-318279] [PMID: 32034004]
[5]
Kogo, R.; Shimamura, T.; Mimori, K.; Kawahara, K.; Imoto, S.; Sudo, T.; Tanaka, F.; Shibata, K.; Suzuki, A.; Komune, S.; Miyano, S.; Mori, M. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res., 2011, 71(20), 6320-6326.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-1021] [PMID: 21862635]
[6]
Tang, J.; Yan, T.; Bao, Y.; Shen, C.; Yu, C.; Zhu, X.; Tian, X.; Guo, F.; Liang, Q.; Liu, Q.; Zhong, M.; Chen, J.; Ge, Z.; Li, X.; Chen, X.; Cui, Y.; Chen, Y.; Zou, W.; Chen, H.; Hong, J.; Fang, J.Y. LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc. Nat. Commun., 2019, 10(1), 3499.
[http://dx.doi.org/10.1038/s41467-019-11447-8] [PMID: 31375671]
[7]
Wang, Y.; Lu, J.H.; Wu, Q.N.; Jin, Y.; Wang, D.S.; Chen, Y.X.; Liu, J.; Luo, X.J.; Meng, Q.; Pu, H.Y.; Wang, Y.N.; Hu, P.S.; Liu, Z.X.; Zeng, Z.L.; Zhao, Q.; Deng, R.; Zhu, X.F.; Ju, H.Q.; Xu, R.H. LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer. Mol. Cancer, 2019, 18(1), 174.
[http://dx.doi.org/10.1186/s12943-019-1105-0] [PMID: 31791342]
[8]
Bian, Z.; Zhang, J.; Li, M.; Feng, Y.; Wang, X.; Zhang, J.; Yao, S.; Jin, G.; Du, J.; Han, W.; Yin, Y.; Huang, S.; Fei, B.; Zou, J.; Huang, Z. LncRNA–FEZF1-AS1 promotes tumor proliferation and metastasis in colorectal cancer by regulating PKM2 signaling. Clin. Cancer Res., 2018, 24(19), 4808-4819.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-2967] [PMID: 29914894]
[9]
Wang, J.; Zhou, J.; Jiang, C.; Zheng, J.; Namba, H.; Chi, P.; Asakawa, T. LNRRIL 6, a novel long noncoding RNA, protects colorectal cancer cells by activating the IL-6– STAT 3 pathway. Mol. Oncol., 2019, 13(11), 2344-2360.
[http://dx.doi.org/10.1002/1878-0261.12538] [PMID: 31246342]
[10]
Zhu, P.; Wu, J.; Wang, Y.; Zhu, X.; Lu, T.; Liu, B.; He, L.; Ye, B.; Wang, S.; Meng, S.; Fan, D.; Wang, J.; Yang, L.; Qin, X.; Du, Y.; Li, C.; He, L.; Ren, W.; Wu, X.; Tian, Y.; Fan, Z. LncGata6 maintains stemness of intestinal stem cells and promotes intestinal tumorigenesis. Nat. Cell Biol., 2018, 20(10), 1134-1144.
[http://dx.doi.org/10.1038/s41556-018-0194-0] [PMID: 30224759]
[11]
Wu, Y.; Yang, X.; Chen, Z.; Tian, L.; Jiang, G.; Chen, F.; Li, J.; An, P.; Lu, L.; Luo, N.; Du, J.; Shan, H.; Liu, H.; Wang, H. m6A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol. Cancer, 2019, 18(1), 87.
[http://dx.doi.org/10.1186/s12943-019-1014-2] [PMID: 30979372]
[12]
Ma, Y.; Yang, Y.; Wang, F.; Moyer, M.P.; Wei, Q.; Zhang, P.; Yang, Z.; Liu, W.; Zhang, H.; Chen, N.; Wang, H.; Wang, H.; Qin, H. Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/β-catenin signalling pathway via suppression of activator protein 2α. Gut, 2016, 65(9), 1494-1504.
[http://dx.doi.org/10.1136/gutjnl-2014-308392] [PMID: 25994219]
[13]
Zhou, Q.; Hou, Z.; Zuo, S.; Zhou, X.; Feng, Y.; Sun, Y.; Yuan, X. LUCAT1 promotes colorectal cancer tumorigenesis by targeting the ribosomal protein L40- MDM 2-p53 pathway through binding withUBA 52. Cancer Sci., 2019, 110(4), 1194-1207.
[http://dx.doi.org/10.1111/cas.13951] [PMID: 30690837]
[14]
Yang, M.H.; Zhao, L.; Wang, L.; Ou-Yang, W.; Hu, S.S.; Li, W.L.; Ai, M.L.; Wang, Y.Q.; Han, Y.; Li, T.T.; Ding, Y.Q.; Wang, S. Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin β3 transcriptional activating and MAPK/AKT signalling. Mol. Cancer, 2019, 18(1), 31.
[http://dx.doi.org/10.1186/s12943-019-0955-9] [PMID: 30823921]
[15]
Liu, L.; Wang, H.J.; Meng, T.; Lei, C.; Yang, X.H.; Wang, Q.S.; Jin, B.; Zhu, J.F. RETRACTED: lncRNA GAS5 inhibits cell migration and invasion and promotes autophagy by targeting miR-222-3p via the GAS5/PTEN-signaling pathway in CRC. Mol. Ther. Nucleic Acids, 2019, 17, 644-656.
[http://dx.doi.org/10.1016/j.omtn.2019.06.009] [PMID: 31400607]
[16]
Ning, X.; Zhao, J.; He, F.; Yuan, Y.; Li, B.; Ruan, J. lncRNA NUTM2A-AS1 Targets the SRSF1/Trim37 signaling pathway to promote the proliferation and invasion of breast cancer. Comput. Math. Methods Med., 2022, 2022, 1-8.
[http://dx.doi.org/10.1155/2022/3299336] [PMID: 35959349]
[17]
Wang, J.; Yu, Z.; Wang, J.; Shen, Y.; Qiu, J.; Zhuang, Z. LncRNA NUTM2A-AS1 positively modulates TET1 and HIF-1A to enhance gastric cancer tumorigenesis and drug resistance by sponging miR-376a. Cancer Med., 2020, 9(24), 9499-9510.
[http://dx.doi.org/10.1002/cam4.3544] [PMID: 33089970]
[18]
Long, J.; Liu, L.; Yang, X.; Zhou, X.; Lu, X.; Qin, L. LncRNA NUTM2A-AS1 aggravates the progression of hepatocellular carcinoma by activating the miR-186-5p/KLF7-mediated Wnt/beta-catenin pathway. Hum. Cell, 2022, 36(1), 312-328.
[http://dx.doi.org/10.1007/s13577-022-00802-5] [PMID: 36242728]
[19]
Wang, J.; Zha, J.; Wang, X. Knockdown of lncRNA NUTM2A-AS1 inhibits lung adenocarcinoma cell viability by regulating the miR-590-5p/METTL3 axis. Oncol. Lett., 2021, 22(5), 798.
[http://dx.doi.org/10.3892/ol.2021.13059] [PMID: 34630705]
[20]
Capallere, C.; Plaza, C.; Bergeron, L.; Serre, C.; Esselin, N.; Meyrignac, C.; Busuttil, V.; Botto, J.; Domloge, N. 338 New 3D engineered skin models to study epidermal renewal and differentiation in vitro, with modulated expression of miR-203, TINCR, or filaggrin. J. Invest. Dermatol., 2016, 136(5), S59-S59.
[http://dx.doi.org/10.1016/j.jid.2016.02.370]
[21]
Xu, T.; Liu, X.; Xia, R.; Yin, L.; Kong, R.; Chen, W.; Huang, M.; Shu, Y. SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer. Oncogene, 2015, 34(45), 5648-5661.
[http://dx.doi.org/10.1038/onc.2015.18] [PMID: 25728677]
[22]
Liu, Y.; Du, Y.; Hu, X.; Zhao, L.; Xia, W. Up-regulation of ceRNA TINCR by SP1 contributes to tumorigenesis in breast cancer. BMC Cancer, 2018, 18(1), 367.
[http://dx.doi.org/10.1186/s12885-018-4255-3] [PMID: 29614984]
[23]
Kouzarides, T. Chromatin modifications and their function. Cell, 2007, 128(4), 693-705.
[http://dx.doi.org/10.1016/j.cell.2007.02.005] [PMID: 17320507]
[24]
Wang, S.; Zang, C.; Xiao, T.; Fan, J.; Mei, S.; Qin, Q.; Wu, Q.; Li, X.; Xu, K.; He, H.H.; Brown, M.; Meyer, C.A.; Liu, X.S. Modeling cis -regulation with a compendium of genome-wide histone H3K27ac profiles. Genome Res., 2016, 26(10), 1417-1429.
[http://dx.doi.org/10.1101/gr.201574.115] [PMID: 27466232]
[25]
Creyghton, M.P.; Cheng, A.W.; Welstead, G.G.; Kooistra, T.; Carey, B.W.; Steine, E.J.; Hanna, J.; Lodato, M.A.; Frampton, G.M.; Sharp, P.A.; Boyer, L.A.; Young, R.A.; Jaenisch, R. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl. Acad. Sci., 2010, 107(50), 21931-21936.
[http://dx.doi.org/10.1073/pnas.1016071107] [PMID: 21106759]
[26]
Zhang, E.; Han, L.; Yin, D.; He, X.; Hong, L.; Si, X.; Qiu, M.; Xu, T.; De, W.; Xu, L.; Shu, Y.; Chen, J. H3K27 acetylation activated-long non-coding RNA CCAT1 affects cell proliferation and migration by regulating SPRY4 and HOXB13 expression in esophageal squamous cell carcinoma. Nucleic Acids Res., 2017, 45(6), 3086-3101.
[http://dx.doi.org/10.1093/nar/gkw1247] [PMID: 27956498]
[27]
Liu, D.; Zhang, H.; Cong, J.; Cui, M.; Ma, M.; Zhang, F.; Sun, H.; Chen, C. H3K27 acetylation-induced lncRNA EIF3J-AS1 improved proliferation and impeded apoptosis of colorectal cancer through miR-3163/YAP1 axis. J. Cell. Biochem., 2020, 121(2), 1923-1933.
[http://dx.doi.org/10.1002/jcb.29427] [PMID: 31709617]
[28]
Liu, B.; Li, J.; Cairns, M.J. Identifying miRNAs, targets and functions. Brief. Bioinform., 2014, 15(1), 1-19.
[http://dx.doi.org/10.1093/bib/bbs075] [PMID: 23175680]
[29]
Cesana, M.; Cacchiarelli, D.; Legnini, I.; Santini, T.; Sthandier, O.; Chinappi, M.; Tramontano, A.; Bozzoni, I. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell, 2011, 147(2), 358-369.
[http://dx.doi.org/10.1016/j.cell.2011.09.028] [PMID: 22000014]
[30]
Tay, Y.; Kats, L.; Salmena, L.; Weiss, D.; Tan, S.M.; Ala, U.; Karreth, F.; Poliseno, L.; Provero, P.; Di Cunto, F.; Lieberman, J.; Rigoutsos, I.; Pandolfi, P.P. Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell, 2011, 147(2), 344-357.
[http://dx.doi.org/10.1016/j.cell.2011.09.029] [PMID: 22000013]
[31]
Tay, Y.; Rinn, J.; Pandolfi, P.P. The multilayered complexity of ceRNA crosstalk and competition. Nature, 2014, 505(7483), 344-352.
[http://dx.doi.org/10.1038/nature12986] [PMID: 24429633]
[32]
Chen, Q.; Chen, S.; Zhao, J.; Zhou, Y.; Xu, L. MicroRNA-126: A new and promising player in lung cancer. Oncol. Lett., 2021, 21(1), 35.
[PMID: 33262827]
[33]
Guo, C.; Sah, J.F.; Beard, L.; Willson, J.K.V.; Markowitz, S.D.; Guda, K. The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer, 2008, 47(11), 939-946.
[http://dx.doi.org/10.1002/gcc.20596] [PMID: 18663744]
[34]
Zhu, Y.; Xu, G.; Patel, A.; McLaughlin, M.M.; Silverman, C.; Knecht, K.A.; Sweitzer, S.; Li, X.; McDonnell, P.; Mirabile, R.; Zimmerman, D.; Boyce, R.; Tierney, L.A.; Hu, E.; Livi, G.P.; Wolf, B.A.; Abdel-Meguid, S.S.; Rose, G.D.; Aurora, R.; Hensley, P.; Briggs, M.; Young, P.R. Cloning, expression, and initial characterization of a novel cytokine-like gene family. Genomics, 2002, 80(2), 144-150.
[http://dx.doi.org/10.1006/geno.2002.6816] [PMID: 12160727]
[35]
Waerner, T.; Alacakaptan, M.; Tamir, I.; Oberauer, R.; Gal, A.; Brabletz, T.; Schreiber, M.; Jechlinger, M.; Beug, H. ILEI: A cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell, 2006, 10(3), 227-239.
[http://dx.doi.org/10.1016/j.ccr.2006.07.020] [PMID: 16959614]
[36]
Gao, Z.H.; Lu, C.; Wang, Z.N.; Song, Y.X.; Zhu, J.L.; Gao, P.; Sun, J.X.; Chen, X.W.; Wang, M.X.; Dong, Y.L.; Xu, H.M. ILEI: A novel marker for epithelial–mesenchymal transition and poor prognosis in colorectal cancer. Histopathology, 2014, 65(4), 527-538.
[http://dx.doi.org/10.1111/his.12435] [PMID: 24738665]
[37]
Schmittgen, T.D.; Livak, K.J. Analyzing real-time PCR data by the comparative CT method. Nat. Protoc., 2008, 3(6), 1101-1108.
[http://dx.doi.org/10.1038/nprot.2008.73] [PMID: 18546601]
[38]
Ding, G.; Li, W.; Liu, J.; Zeng, Y.; Mao, C.; Kang, Y.; Shang, J. LncRNA GHET1 activated by H3K27 acetylation promotes cell tumorigenesis through regulating ATF1 in hepatocellular carcinoma. Biomed. Pharmacother., 2017, 94, 326-331.
[http://dx.doi.org/10.1016/j.biopha.2017.07.046] [PMID: 28772210]
[39]
Bose, D.A.; Donahue, G.; Reinberg, D.; Shiekhattar, R.; Bonasio, R.; Berger, S.L. RNA binding to CBP stimulates histone acetylation and transcription. Cell, 2017, 168(1-2), 135-149.e22.
[http://dx.doi.org/10.1016/j.cell.2016.12.020] [PMID: 28086087]
[40]
Liu, K.; Yao, H.; Wen, Y.; Zhao, H.; Zhou, N.; Lei, S.; Xiong, L. Functional role of a long non-coding RNA LIFR-AS1/miR-29a/TNFAIP3 axis in colorectal cancer resistance to pohotodynamic therapy. Biochim. Biophys. Acta Mol. Basis Dis., 2018, 1864(9)(9 Pt B), 2871-2880.
[http://dx.doi.org/10.1016/j.bbadis.2018.05.020] [PMID: 29807108]
[41]
Chen, X.; Zeng, K.; Xu, M.; Hu, X.; Liu, X.; Xu, T.; He, B.; Pan, Y.; Sun, H.; Wang, S. SP1-induced lncRNA-ZFAS1 contributes to colorectal cancer progression via the miR-150-5p/VEGFA axis. Cell Death Dis., 2018, 9(10), 982.
[http://dx.doi.org/10.1038/s41419-018-0962-6] [PMID: 30250022]
[42]
Ying, H.; Jin, Y.; Guo, Y.; Li, Q.; Ruan, M.; Zhu, W.; Yang, C.; Li, Q.; Zheng, L. Long non-coding RNA NUT family member 2A-antisense RNA 1 sponges microRNA-613 to increase the resistance of gastric cancer cells to matrine through regulating oxidative stress and vascular endothelial growth factor A. Aging, 2022, 14(12), 5153-5162.
[http://dx.doi.org/10.18632/aging.204135] [PMID: 35771149]
[43]
Ye, P.; Lv, X.; Aizemaiti, R.; Cheng, J.; Xia, P.; Di, M. H3K27ac-activated LINC00519 promotes lung squamous cell carcinoma progression by targeting miR-450b-5p/miR-515-5p/YAP1 axis. Cell Prolif., 2020, 53(5), e12797.
[http://dx.doi.org/10.1111/cpr.12797] [PMID: 32297697]
[44]
Chen, F.; Qi, S.; Zhang, X.; Wu, J.; Yang, X.; Wang, R. lncRNA PLAC2 activated by H3K27 acetylation promotes cell proliferation and invasion via the activation of Wnt/β-catenin pathway in oral squamous cell carcinoma. Int. J. Oncol., 2019, 54(4), 1183-1194.
[http://dx.doi.org/10.3892/ijo.2019.4707] [PMID: 30720068]
[45]
Dong, H.; Wang, W.; Mo, S.; Chen, R.; Zou, K.; Han, J.; Zhang, F.; Hu, J. RETRACTED ARTICLE: SP1-induced lncRNA AGAP2-AS1 expression promotes chemoresistance of breast cancer by epigenetic regulation of MyD88. J. Exp. Clin. Cancer Res., 2018, 37(1), 202.
[http://dx.doi.org/10.1186/s13046-018-0875-3] [PMID: 30157918]
[46]
Schmitt, A.M.; Chang, H.Y. Long noncoding RNAs in cancer pathways. Cancer Cell, 2016, 29(4), 452-463.
[http://dx.doi.org/10.1016/j.ccell.2016.03.010] [PMID: 27070700]
[47]
Liu, X.; Ma, J.; Xu, F.; Li, L. TINCR suppresses proliferation and invasion through regulating miR-544a/FBXW7 axis in lung cancer. Biomed. Pharmacother., 2018, 99, 9-17.
[http://dx.doi.org/10.1016/j.biopha.2018.01.049] [PMID: 29324317]
[48]
Dong, H.; Hu, J.; Zou, K.; Ye, M.; Chen, Y.; Wu, C.; Chen, X.; Han, M. RETRACTED ARTICLE: Activation of LncRNA TINCR by H3K27 acetylation promotes Trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast Cancer. Mol. Cancer, 2019, 18(1), 3.
[http://dx.doi.org/10.1186/s12943-018-0931-9] [PMID: 30621694]

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