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LY6K-AS lncRNA is a lung adenocarcinoma prognostic biomarker and regulator of mitotic progression

Oncogene volume 40, pages 2463–2478 (2021)Cite this article

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Abstract

Recent advances in genomics unraveled several actionable mutational drivers in lung cancer, leading to promising therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. However, the tumors’ acquired resistance to the newly-developed as well as existing therapies restricts life quality improvements. Therefore, we investigated the noncoding portion of the human transcriptome in search of alternative actionable targets. We identified an antisense transcript, LY6K-AS, with elevated expression in lung adenocarcinoma (LUAD) patients, and its higher expression in LUAD patients predicts poor survival outcomes. LY6K-AS abrogation interfered with the mitotic progression of lung cancer cells resulting in unfaithful chromosomal segregation. LY6K-AS interacts with and stabilizes 14-3-3 proteins to regulate the transcription of kinetochore and mitotic checkpoint proteins. We also show that LY6K-AS regulates the levels of histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of kinetochore members. Cisplatin treatment and LY6K-AS silencing affect many common pathways enriched in cell cycle-related functions. LY6K-AS silencing affects the growth of xenografts derived from wildtype and cisplatin-resistant lung cancer cells. Collectively, these data indicate that LY6K-AS silencing is a promising therapeutic option for LUAD that inhibits oncogenic mitotic progression.

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Fig. 1: Identification of clinically-relevant antisense lncRNAs in LUAD.
Fig. 2: LY6K-AS KD perturbs proliferation and cell cycle progression of LUAD cell lines.
Fig. 3: LY6K-AS KD interferes with mitosis and chromosomal segregation.
Fig. 4: LY6K-AS interacts with YWHAG.
Fig. 5: LY6K-AS regulates YWHAG stability.
Fig. 6: LY6K-AS expression sensitizes chemotherapy-resistant cell lines.

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Data availability

The data associated with this publication have been deposited in GEO: GSE164419.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    Article  Google Scholar 

  3. de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res. 2018;7:220–33.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10:1243–60.

    Article  PubMed  Google Scholar 

  5. Galluzzi L, Vitale I, Michels J, Brenner C, Szabadkai G, Harel-Bellan A, et al. Systems biology of cisplatin resistance: past, present and future. Cell Death Dis. 2014;5:e1257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL, et al. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389:299–311.

    Article  CAS  PubMed  Google Scholar 

  7. Wu SG, Shih JY. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer. Mol Cancer. 2018;17:38.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J. 2018;24:47–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kornienko AE, Dotter CP, Guenzl PM, Gisslinger H, Gisslinger B, Cleary C, et al. Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans. Genome Biol. 2016;17:14.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47:199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell. 2008;32:232–46.

    Article  CAS  PubMed  Google Scholar 

  13. Ohhata T, Senner CE, Hemberger M, Wutz A. Lineage-specific function of the noncoding Tsix RNA for Xist repression and Xi reactivation in mice. Genes Dev. 2011;25:1702–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29:452–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Akhade VS, Pal D, Kanduri C. Long noncoding RNA: genome organization and mechanism of action. Adv Exp Med Biol. 2017;1008:47–74.

    Article  CAS  PubMed  Google Scholar 

  16. Wu H, Yang L, Chen LL. The diversity of long noncoding RNAs and their generation. Trends Genet. 2017;33:540–52.

    Article  CAS  PubMed  Google Scholar 

  17. Subhash S, Mishra K, Akhade VS, Kanduri M, Mondal T, Kanduri C. H3K4me2 and WDR5 enriched chromatin interacting long non-coding RNAs maintain transcriptionally competent chromatin at divergent transcriptional units. Nucleic Acids Res. 2018;46:9384–9400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Balbin OA, Malik R, Dhanasekaran SM, Prensner JR, Cao X, Wu YM, et al. The landscape of antisense gene expression in human cancers. Genome Res. 2015;25:1068–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pandey GK, Mitra S, Subhash S, Hertwig F, Kanduri M, Mishra K, et al. The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. Cancer Cell. 2014;26:722–37.

    Article  CAS  PubMed  Google Scholar 

  20. Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73:1180–9.

    Article  CAS  PubMed  Google Scholar 

  21. Ali MM, Akhade VS, Kosalai ST, Subhash S, Statello L, Meryet-Figuiere M, et al. PAN-cancer analysis of S-phase enriched lncRNAs identifies oncogenic drivers and biomarkers. Nat Commun. 2018;9:883.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Marchese FP, Grossi E, Marin-Bejar O, Bharti SK, Raimondi I, Gonzalez J, et al. A long noncoding RNA regulates sister chromatid cohesion. Mol Cell. 2016;63:397–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. White NM, Cabanski CR, Silva-Fisher JM, Dang HX, Govindan R, Maher CA. Transcriptome sequencing reveals altered long intergenic non-coding RNAs in lung cancer. Genome Biol. 2014;15:429.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ooi AT, Gower AC, Zhang KX, Vick JL, Hong L, Nagao B, et al. Molecular profiling of premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis. Cancer Prev Res. 2014;7:487–95.

    Article  CAS  Google Scholar 

  25. Montes M, Nielsen MM, Maglieri G, Jacobsen A, Hojfeldt J, Agrawal-Singh S, et al. The lncRNA MIR31HG regulates p16(INK4A) expression to modulate senescence. Nat Commun. 2015;6:6967.

    Article  CAS  PubMed  Google Scholar 

  26. Isaka T, Nestor AL, Takada T, Allison DC. Chromosomal variations within aneuploid cancer lines. J Histochem Cytochem. 2003;51:1343–53.

    Article  CAS  PubMed  Google Scholar 

  27. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38:576–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mahale S, Kumar M, Sharma A, Babu A, Ranjan S, Sachidanandan C, et al. The light intermediate chain 2 subpopulation of dynein regulates mitotic spindle orientation. Sci Rep. 2016;6:22.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chen DY, Dai DF, Hua Y, Qi WQ. p53 suppresses 14-3-3gamma by stimulating proteasome-mediated 14-3-3gamma protein degradation. Int J Oncol. 2015;46:818–24.

    Article  CAS  PubMed  Google Scholar 

  31. Urano T, Saito T, Tsukui T, Fujita M, Hosoi T, Muramatsu M, et al. Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth. Nature. 2002;417:871–5.

    Article  CAS  PubMed  Google Scholar 

  32. Roeten MSF, Cloos J, Jansen G. Positioning of proteasome inhibitors in therapy of solid malignancies. Cancer Chemother Pharmacol. 2018;81:227–43.

    Article  CAS  PubMed  Google Scholar 

  33. Winter S, Simboeck E, Fischle W, Zupkovitz G, Dohnal I, Mechtler K, et al. 14-3-3 proteins recognize a histone code at histone H3 and are required for transcriptional activation. EMBO J. 2008;27:88–99.

    Article  CAS  PubMed  Google Scholar 

  34. Vedadi M, Blazer L, Eram MS, Barsyte-Lovejoy D, Arrowsmith CH, Hajian T. Targeting human SET1/MLL family of proteins. Protein Sci. 2017;26:662–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lischetti T, Nilsson J. Regulation of mitotic progression by the spindle assembly checkpoint. Mol Cell Oncol. 2015;2:e970484.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Holland AJ, Cleveland DW. Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep. 2012;13:501–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gavet O, Pines J. Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis. Dev Cell. 2010;18:533–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nishimura K, Johmura Y, Deguchi K, Jiang Z, Uchida KSK, Suzuki N, et al. Cdk1-mediated DIAPH1 phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase. Nat Commun. 2019;10:981.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lara-Gonzalez P, Moyle MW, Budrewicz J, Mendoza-Lopez J, Oegema K, Desai A. The G2-to-M transition is ensured by a dual mechanism that protects cyclin B from degradation by Cdc20-activated APC/C. Dev Cell. 2019;51:313–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dominguez-Brauer C, Thu KL, Mason JM, Blaser H, Bray MR, Mak TW. Targeting mitosis in cancer: emerging strategies. Mol Cell. 2015;60:524–36.

    Article  CAS  PubMed  Google Scholar 

  41. Siemeister G, Mengel A, Fernandez-Montalvan AE, Bone W, Schroder J, Zitzmann-Kolbe S, et al. Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo. Clin Cancer Res. 2019;25:1404–14.

    Article  CAS  PubMed  Google Scholar 

  42. Uetake Y, Sluder G. Prolonged prometaphase blocks daughter cell proliferation despite normal completion of mitosis. Curr Biol. 2010;20:1666–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Giannakakou P, Robey R, Fojo T, Blagosklonny MV. Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity. Oncogene. 2001;20:3806–13.

    Article  CAS  PubMed  Google Scholar 

  44. Gardino AK, Yaffe MB. 14-3-3 proteins as signaling integration points for cell cycle control and apoptosis. Semin Cell Dev Biol. 2011;22:688–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hosing AS, Kundu ST, Dalal SN. 14-3-3 Gamma is required to enforce both the incomplete S phase and G2 DNA damage checkpoints. Cell Cycle. 2008;7:3171–9.

    Article  CAS  PubMed  Google Scholar 

  46. Qi W, Liu X, Qiao D, Martinez JD. Isoform-specific expression of 14-3-3 proteins in human lung cancer tissues. Int J Cancer. 2005;113:359–63.

    Article  CAS  PubMed  Google Scholar 

  47. Raungrut P, Wongkotsila A, Lirdprapamongkol K, Svasti J, Geater SL, Phukaoloun M, et al. Prognostic significance of 14-3-3gamma overexpression in advanced non-small cell lung cancer. Asian Pac J Cancer Prev. 2014;15:3513–8.

    Article  PubMed  Google Scholar 

  48. Kasahara K, Goto H, Izawa I, Kiyono T, Watanabe N, Elowe S, et al. PI 3-kinase-dependent phosphorylation of Plk1-Ser99 promotes association with 14-3-3gamma and is required for metaphase-anaphase transition. Nat Commun. 2013;4:1882.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bose A, Dalal SN. 14-3-3 proteins mediate the localization of Centrin2 to centrosome. J Biosci. 2019;44:42–10.

    Article  PubMed  Google Scholar 

  50. Kasahara K, Goto H, Enomoto M, Tomono Y, Kiyono T, Inagaki M. 14-3-3gamma mediates Cdc25A proteolysis to block premature mitotic entry after DNA damage. EMBO J. 2010;29:2802–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Macdonald N, Welburn JP, Noble ME, Nguyen A, Yaffe MB, Clynes D, et al. Molecular basis for the recognition of phosphorylated and phosphoacetylated histone h3 by 14-3-3. Mol Cell. 2005;20:199–211.

    Article  CAS  PubMed  Google Scholar 

  52. Zippo A, Serafini R, Rocchigiani M, Pennacchini S, Krepelova A, Oliviero S. Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell. 2009;138:1122–36.

    Article  CAS  PubMed  Google Scholar 

  53. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  54. Lassmann T, Hayashizaki Y, Daub CO. SAMStat: monitoring biases in next-generation sequencing data. Bioinformatics. 2011;27:130–1.

    Article  CAS  PubMed  Google Scholar 

  55. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

    Article  CAS  PubMed  Google Scholar 

  56. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article  CAS  PubMed  Google Scholar 

  57. Subhash S, Kanduri C. GeneSCF: a real-time based functional enrichment tool with support for multiple organisms. BMC Bioinfor. 2016;17:365.

    Article  Google Scholar 

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Acknowledgements

This work was supported by the grants from Knut and Alice Wallenberg Foundation [KAW2014.0057]; Swedish Foundation for Strategic Research [RB13-0204]; Swedish Cancer Research foundation [Cancerfonden: Kontrakt no. CAN2018/591]; Swedish Research Council [2017-02834]; Barncancerfonden [PR2018-0090]; Ingabritt Och Arne Lundbergs forskningsstiftelse and LUA/ ALF (to CK). The Proteomics Core Facility at Gothenburg University, performed the analysis for protein identification. We acknowledge the Centre for Cellular Imaging at the University of Gothenburg for assisting in microscopy.

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Authors and Affiliations

  1. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden

    Mohamad Moustafa Ali, Mirco Di Marco, Sagar Mahale, Daniel Jachimowicz, Subazini Thankaswamy Kosalai, Silke Reischl, Luisa Statello, Kankadeb Mishra & Chandrasekhar Kanduri

  2. Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden

    Catarina Darnfors

  3. Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden

    Meena Kanduri

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  1. Mohamad Moustafa Ali
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Contributions

Conceptualization—CK and MMA; Methodology—MMA, STK, SM, MDM, SR, DJ, CD, KM, and LS; Investigations—MMA, STK, SM, MDM, SR, DJ, CD, KM, and LS; Writing—original drafts- MMA; Writing—review and editing- MMA and CK; Funding acquisition, CK; Supervision, CK.

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Correspondence to Chandrasekhar Kanduri.

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Ali, M.M., Di Marco, M., Mahale, S. et al. LY6K-AS lncRNA is a lung adenocarcinoma prognostic biomarker and regulator of mitotic progression. Oncogene 40, 2463–2478 (2021). https://doi.org/10.1038/s41388-021-01696-7

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