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LncRNA SLC25A21-AS1 increases the chemosensitivity and inhibits the progression of ovarian cancer by upregulating the expression of KCNK4

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Abstract

Owing to high mortality rate, ovarian cancer seriously threatens women’s health. Extensive abdominal metastasis and chemoresistance are the leading causes of ovarian cancer deaths. Through lncRNA sequencing, our previous study identified lncRNA SLC25A21-AS1, which was significantly downregulated in chemoresistant ovarian cancer cells. In this study, we aimed to evaluate the role and mechanism of SLC25A21-AS1 in ovarian cancer. The expression of SLC25A21-AS1 was analyzed by qRT-PCR and online database GEPIA. The biological functions of SLC25A21-AS1 and KCNK4 were analyzed by CCK-8, transwell, and flow cytometry. The specific mechanism was analyzed by RNA-sequencing, RNA binding protein immunoprecipitation, rescue experiments, and bioinformatic analysis. SLC25A21-AS1 was decreased in ovarian cancer tissues and cell lines. Overexpression of SLC25A21-AS1 enhanced the sensitivity of ovarian cancer cells to paclitaxel and cisplatin, and inhibited cell proliferation, invasion, and migration, while SLC25A21-AS1-silencing showed the opposite effect. Potassium channel subfamily K member 4 (KCNK4) was significantly up-regulated upon enforced expression of SLC25A21-AS1. Overexpression of KCNK4 inhibited cell proliferation, invasion, migration ability, and enhanced the sensitivity of ovarian cancer cells to paclitaxel and cisplatin. Meanwhile, KNCK4-overexpression rescued the promotive effect of SLC25A21-AS1-silencing on cell proliferation, invasion and migration. In addition, SLC25A21-AS1 could interact with the transcription factor Enhancer of Zeste Homolog 2 (EZH2), while EZH2 knockdown increased the expression of KCNK4 in some of the ovarian cancer cell lines. SLC25A21-AS1 enhanced the chemosensitivity and inhibited the proliferation, migration, and invasion ability of ovarian cancer cells at least partially by blocking EZH2-mediated silencing of KCNK4.

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Data availability

The data supporting this study are available from the corresponding author upon reasonable request.

Abbreviations

CCK-8 :

Cell Counting Kit-8

CHIP :

Chromatin immunoprecipitation

PTX :

Paclitaxel

DDP :

Cisplatin

EZH2 :

Enhancer of Zeste homolog 2

FISH :

Fluorescence in situ hybridization

GEPIA :

Gene expression profiling interactive analysis

GO :

Gene ontology

H3K27me3 :

Trimethylation of lysine 27 on histone 3

KCNK4 :

Potassium channel subfamily K member 4

IC50 :

The half maximal inhibitory concentration

lncRNA :

Long noncoding RNA

PRC2 :

Polycomb complex 2

qRT-PCR :

Real-time quantitative PCR

RIP :

RNA binding protein immunoprecipitation

TRAAK :

TWIK-related arachidonic acid-stimulated channel

References

  • Beltran L, Beltran M, Aguado A, Gisselmann G, Hatt H (2013) 2-Aminoethoxydiphenyl borate activates the mechanically gated human KCNK channels KCNK 2 (TREK-1), KCNK 4 (TRAAK), and KCNK 10 (TREK-2). Front Pharmacol 4:63

    Article  PubMed  PubMed Central  Google Scholar 

  • Berek JS, Renz M, Kehoe S, Kumar L, Friedlander M (2021) Cancer of the ovary, fallopian tube, and peritoneum: 2021 update. Int J Gynaecol Obstet 155(Suppl 1):61–85

    Article  PubMed  PubMed Central  Google Scholar 

  • Chien J, Kuang R, Landen C, Shridhar V (2013) Platinum-sensitive recurrence in ovarian cancer: the role of tumor microenvironment. Front Oncol 3:251

    Article  PubMed  PubMed Central  Google Scholar 

  • Comet I, Riising EM, Leblanc B, Helin K (2016) Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer 16:803–810

    Article  CAS  PubMed  Google Scholar 

  • Deng SJ, Chen HY, Ye Z, Deng SC, Zhu S, Zeng Z, He C, Liu ML, Huang K, Zhong JX, Xu FY, Li Q, Liu Y, Wang CY, Zhao G (2018) Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription. Oncogene 37:5811–5828

    Article  CAS  PubMed  Google Scholar 

  • Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Iny Stein T, Rosen N, Kohn A, Twik M, Safran M, Lancet D, Cohen D (2017) GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford). 2017:bax028

    Article  PubMed  PubMed Central  Google Scholar 

  • Fu LL, Li CJ, Xu Y, Li LY, Zhou X, Li DD, Chen SX, Wang FG, Zhang XY, Zheng LW (2017) Role of lncRNAs as Novel biomarkers and therapeutic targets in ovarian cancer. Crit Rev Eukaryot Gene Expr 27:183–195

    Article  PubMed  Google Scholar 

  • He Y, Wang H, Yan M, Yang X, Shen R, Ni X, Chen X, Yang P, Chen M, Lu X, Shao G, Zhou X, Shao Q (2018) High LIN28A and PLK4 coexpression is associated with poor prognosis in epithelial ovarian cancer. Mol Med Rep 18:5327–5336

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Hu Y, Jin Z, Shen Z (2018) LncRNA snaR upregulates GRB2-associated binding protein 2 and promotes proliferation of ovarian carcinoma cells. Biochem Biophys Res Commun 503:2028–2032

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Zhang Y, Xu Y, Yang S, Li B, Huang L, Lou G (2020) Comprehensive analysis of the expression of sodium/potassium-ATPase alpha subunits and prognosis of ovarian serous cystadenocarcinoma. Cancer Cell Int 20:309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim KH, Roberts CW (2016) Targeting EZH2 in cancer. Nat Med 22:128–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lanczky A, Gyorffy B (2021) Web-based survival analysis tool tailored for medical research (KMplot): development and implementation. J Med Internet Res 23:e27633

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Q, Dong C, Cui J, Wang Y, Hong X (2018) Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme. J Exp Clin Cancer Res 37:265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, Huang L, Wei L, Zhang B, Zhong S, Ou Y, Wen C, Huang S (2020) KCNH3 predicts poor prognosis and promotes progression in ovarian cancer. Onco Targets Ther 13:10323–10333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin X, Wu JF, Wang DM, Zhang J, Zhang WJ, Xue G (2020) The correlation and role analysis of KCNK2/4/5/15 in human papillary thyroid carcinoma microenvironment. J Cancer 11:5162–5176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X, Wei L, Zhao B, Cai X, Dong C, Yin F (2018) Low expression of KCNN3 may affect drug resistance in ovarian cancer. Mol Med Rep 18:1377–1386

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Li C, Fang L, Wang L, Liu H, Tian H, Zheng Y, Fan T, He J (2022) Lipid metabolism-related lncRNA SLC25A21-AS1 promotes the progression of oesophageal squamous cell carcinoma by regulating the NPM1/c-Myc axis and SLC25A21 expression. Clin Transl Med 12:e944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao C, Wang X, Liu Y, Wang M, Yan B, Jiang Y, Shi Y, Shen Y, Liu X, Lai W, Yang R, Xiao D, Cheng Y, Liu S, Zhou H, Cao Y, Yu W, Muegge K, Yu H, Tao Y (2018) A G3BP1-interacting lncrna promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Res 78:3484–3496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rabani M, Raychowdhury R, Jovanovic M, Rooney M, Stumpo DJ, Pauli A, Hacohen N, Schier AF, Blackshear PJ, Friedman N, Amit I, Regev A (2014) High-resolution sequencing and modeling identifies distinct dynamic RNA regulatory strategies. Cell 159:1698–1710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. CA Cancer J Clin 73:17–48

    Article  PubMed  Google Scholar 

  • St Laurent G, Wahlestedt C, Kapranov P (2015) The landscape of long noncoding RNA classification. Trends Genet 31:239–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Q, Hao Q, Prasanth KV (2018) Nuclear long noncoding RNAs: key regulators of gene expression. Trends Genet 34:142–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Wang C, Xu H, Xie H (2020) Long non-coding RNA SLC25A21-AS1 Promotes multidrug resistance in nasopharyngeal carcinoma by regulating miR-324-3p/IL-6 Axis. Cancer Manag Res 12:3949–3957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Wang Z, Wang L (2022) Long noncoding RNA solute carrier family 25 member 21 antisense RNA 1 inhibits cell malignant behaviors and enhances radiosensitivity of gastric cancer cells by upregulating synuclein gamma expression. Tohoku J Exp Med 257:225–239

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, Hu L, Liang Y, Li J, Wang K, Chen X, Meng H, Guan X, Yang K, Bai Y (2017) Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2. Mol Cancer 16:150

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu J, Wu J, Fu C, Teng F, Liu S, Dai C, Shen R, Jia X (2018) Multidrug resistant lncRNA profile in chemotherapeutic sensitive and resistant ovarian cancer cells. J Cell Physiol 233:5034–5043

    Article  CAS  PubMed  Google Scholar 

  • Zhang G, Li Y, Li N, Shen LF, Li Z (2022) Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients. Aging (albany NY) 14:2348–2366

    Article  CAS  PubMed  Google Scholar 

  • Zhao J, Du P, Cui P, Qin Y, Hu C, Wu J, Zhou Z, Zhang W, Qin L, Huang G (2018) LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer. Oncogene 37:4094–4109

    Article  CAS  PubMed  Google Scholar 

  • Zhu M, Li K, Zhang J (2022) Gliomas with downregulation of lncRNA SLC25A21-AS1 carry a dismal prognosis and an accelerated progression in cell proliferation, migration and invasion. Mol Biotechnol 64:936–944

    Article  CAS  PubMed  Google Scholar 

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Funding

The study was financially supported by the National Natural Science Foundation of China (81572556, 81872126, J.X.), Jiangsu provincial key research and development program (BE2019621, J.X. and BE2020753, X.J.) and Jiangsu Province Capability Improvement Project through Science, Technology and Education Jiangsu Provincial Medical Key Discipline (ZDXK202211).

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Author notes

  1. Ke Huang and Xiyi Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), 123 Tianfei Alley, Mochou Road, Nanjing, 210004, China

    Ke Huang, Xiyi Chen, Zhe Geng, Xueyou Xiong, Yu Cong, Xinxing Pan, Siyu Liu, Lili Ge, Juan Xu & Xuemei Jia

Authors
  1. Ke Huang
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  2. Xiyi Chen
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  3. Zhe Geng
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  4. Xueyou Xiong
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  5. Yu Cong
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  7. Siyu Liu
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  8. Lili Ge
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  9. Juan Xu
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  10. Xuemei Jia
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Contributions

X.M.J. and J.X.: conceptualization, supervision, funding acquisition, writing-review and editing; L.L.G.: methodology, formal analysis, investigation, writing-review and editing; K.H. and X.Y.C.: methodology, formal analysis, investigation, writing-original draft; Z.G., X.Y.X., Y.C., X.X.P., and S.Y.L.: investigation, formal analysis; all authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Lili Ge, Juan Xu or Xuemei Jia.

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Ethics approval and consent to participate

This study used the patient’ tissues was performed according to the declaration of Helsinki and was approved by the Ethics Committee of Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital).

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Not applicable.

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The authors declare no competing interests.

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Huang, K., Chen, X., Geng, Z. et al. LncRNA SLC25A21-AS1 increases the chemosensitivity and inhibits the progression of ovarian cancer by upregulating the expression of KCNK4. Funct Integr Genomics 23, 110 (2023). https://doi.org/10.1007/s10142-023-01035-x

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  • DOI: https://doi.org/10.1007/s10142-023-01035-x

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