Article | Published:

MALAT1-KTN1-EGFR regulatory axis promotes the development of cutaneous squamous cell carcinoma

Subjects

Abstract

Long noncoding RNAs (LncRNAs), including MALAT1, are critical regulators of tumor development. However, the roles and molecular mechanisms of LncRNAs in cutaneous squamous cell carcinoma (cSCC) remain underexplored. In this study, functional studies using in vitro cellular and in vivo xenograft models confirmed the pro-carcinogenic roles of MALAT1 in cSCC. Further, MALAT1 was identified to regulate epidermal growth factor receptor (EGFR) protein expression but did not affect EGFR mRNA expression. Transcriptomic sequencing identified kinectin 1 (KTN1) as the key mediator for MALAT1 regulation of EGFR. Mechanistic study revealed that MALAT1 interacts with c-MYC to form a complex and directly binds to the promoter region of KTN1 gene and enhances its transactivation to positively regulate EGFR protein expression. Our findings, therefore, establish a novel c-MYC-assisted MALAT1-KTN1-EGFR axis, which contributes to cSCC development and may serve as novel target for therapeutic intervention.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Edited by R. A. Knight

References

  1. 1.

    Lomas A, Leonardi‐Bee J, Bath‐Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol. 2012;166:1069–80.

  2. 2.

    Cheng J, Yan S. Prognostic variables in high‐risk cutaneous squamous cell carcinoma: a review. J Cutan Pathol. 2016;43:994–1004.

  3. 3.

    Lee CS, Bhaduri A, Mah A, Johnson WL, Ungewickell A, Aros CJ, et al. Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma. Nat Genet. 2014. https://doi.org/10.1038/ng.3091.

  4. 4.

    Gutschner T, Diederichs S. The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol. 2012;9:703–19.

  5. 5.

    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.

  6. 6.

    Yang F, Zhang H, Mei Y, Wu M. Reciprocal regulation of HIF-1α and lincRNA-p21 modulates the Warburg effect. Mol Cell. 2014;53:88–100.

  7. 7.

    Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22:8031–41.

  8. 8.

    Xu C, Yang M, Tian J, Wang X, Li Z. MALAT-1: a long non-coding RNA and its important 3’end functional motif in colorectal cancer metastasis. Int J Oncol. 2011;39:169–75.

  9. 9.

    Gutschner T, Hämmerle M, Diederichs S. MALAT1—a paradigm for long noncoding RNA function in cancer. J Mol Med. 2013;91:791–801.

  10. 10.

    Gutschner T, Hämmerle 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.

  11. 11.

    Hu Q, Kwon Y-S, Nunez E, Cardamone MD, Hutt KR, Ohgi KA, et al. Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules. Proc Natl Acad Sci. 2008;105:19199–204.

  12. 12.

    Chen G, Wang Z, Wang D, Qiu C, Liu M, Chen X, et al. LncRNADisease: a database for long-non-coding RNA-associated diseases. Nucl Acids Res. 2012;41:D983–6.

  13. 13.

    Wang J, Zhao L, Lin P, Su X, Chen S, Huang L, et al. GenCLiP 2.0: a web server for functional clustering of genes and construction of molecular networks based on free terms. Bioinformatics. 2014;30:2534–6.

  14. 14.

    Merlino G, Xu YH, Ishii S, Clark AJL, Semba K, Toyoshima K, et al. Amplification and enhanced expression of the epidermal growth factor receptor gene in A431 human carcinoma cells. Science. 1984;224:417–9.

  15. 15.

    Arun G, Diermeier S, Akerman M, Chang KC, Wilkinson JE, Hearn S, et al. Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev. 2016;30:86–95.

  16. 16.

    Ong L, Lin P, Zhang X, Chia S, Yu H. Kinectin-dependent assembly of translation elongation factor-1 complex on endoplasmic reticulum regulates protein synthesis. J Biol Chem. 2006;281:33621–34.

  17. 17.

    Loots GG, Ovcharenko I. rVISTA 2.0: evolutionary analysis of transcription factor binding sites. Nucl Acids Res. 2004;32:W217–21. (Web Server issue)

  18. 18.

    Schmitz SU, Grote P, Herrmann BG. Mechanisms of long noncoding RNA function in development and disease. Cell Mol Life Sci. 2016;73:2491–509.

  19. 19.

    El-Abaseri TB, Fuhrman J, Trempus C, Shendrik I, Tennant RW, Hansen LA. Chemoprevention of UV light-induced skin tumorigenesis by inhibition of the epidermal growth factor receptor. Cancer Res. 2005;65:3958–65.

  20. 20.

    Lewis CM, Glisson BS, Feng L, Wan F, Tang X, Wistuba II, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res. 2012;18:1435–46.

  21. 21.

    Gong C, Li Z, Ramanujan K, Clay I, Zhang Y, Lemire-Brachat S, et al. A long non-coding RNA, LncMyoD, regulates skeletal muscle differentiation by blocking IMP2-mediated mRNA translation. Dev Cell. 2015;34:181–91.

  22. 22.

    Day TF, Mewani RR, Starr J, Li X, Chakravarty D, Ressom H, et al. Transcriptome and proteome analyses of TNFAIP8 knockdown cancer cells reveal new insights into molecular determinants of cell survival and tumor progression. Methods Mol Biol. 2017;1513:83–100.

  23. 23.

    Liu D, Zhu Y, Pang J, Xie W, Feng X, Guo Y. Knockdown of long non‐coding RNA MALAT1 inhibits growth and motility of human hepatoma cells via modulation of miR‐195. J Cell Biochem. 2018;119:1368–80.

  24. 24.

    Franovic A, Gunaratnam L, Smith K, Robert I, Patten DA, Lee S. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci USA. 2007;104:13092–7.

  25. 25.

    Luo F, Sun B, Li H, Xu Y, Liu Y, Liu X, et al. A MALAT1/HIF-2α feedback loop contributes to arsenite carcinogenesis. Oncotarget. 2016;7:5769–87.

  26. 26.

    Kumar J, Yu H, Sheetz MP. Kinectin, an essential anchor for kinesin-driven vesicle motility. Science. 1995;267:1834–7.

  27. 27.

    Taub R, Kirsch I, Morton C, Lenoir G, Swan D, Tronick SR, et al. Translocation of the c-MYC- gene into the immunoglobulin heavy-chain locus in human Burkitt’s lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci USA. 1982;79:7837–41.

  28. 28.

    Eilers M, Eisenman RN. Myc’s broad reach. Genes Dev. 2008;22:2755–66.

  29. 29.

    Lohcharoenkal W, Harada M, Loven J, Meisgen F, Landen NX, Zhang L, et al. MicroRNA-203 inversely correlates with differentiation grade, targets c-MYC and functions as a tumor suppressor in cSCC. J Invest Dermatol. 2016;136:2485–94.

  30. 30.

    Blackwood EM, Eisenman RN. Max-A-helix-loophelix zipper protein that forms a sequence-specific DNA binding complex with myc. Science. 1991;251:1211–7.

  31. 31.

    Zeller KI, Zhao X, Lee CWH, Chiu KP, Yao F, Yustein JT, et al. Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci USA. 2006;103:17834–9.

  32. 32.

    Dang CV, Donnell KAO, Zeller KI, Nguyen T, Osthus RC, Li F. The c-Myc target gene network. Semin Cancer Biol. 2006;16:253–64.

  33. 33.

    Barsytelovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL, et al. The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res. 2006;66:5330–7.

  34. 34.

    Yang F, Xue X, Bi J, Zheng L, Zhi K, Gu Y, et al. Long noncoding RNA CCAT1, which could be activated by c-Myc, promotes the progression of gastric carcinoma. J Cancer Res Clin Oncol. 2013;139:437–45.

  35. 35.

    Hung C, Wang L, Yu Y, Chen H, Srivastava S, Petrovics G, et al. A long noncoding RNA connects c-Myc to tumor metabolism. Proc Natl Acad Sci USA. 2014;111:18697–702.

  36. 36.

    Sun H, Lin DC, Cao Q, Pang B, Gae DD, Lee VK, et al. Identification of a novel SYK/c-MYC/MALAT1 signaling pathway and its potential therapeutic value in ewing sarcoma. Clin Cancer Res. 2017;23:4376–87.

  37. 37.

    Button KS, Ioannidis JPA, Mokrysz C, Nosek BA, Flint J, Robinson ESJ, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14:365–76.

  38. 38.

    Krzywinski M, Altman N. Points of significance: Power and sample size. Nat Methods. 2013;10:1139–40.

Download references

Acknowledgements

The work described in this paper was substantially supported by grants from the National Natural Science Foundation of China (Grant Nos. 81573076, 81172634; http://www.nsfc.gov.cn/); a grant from Guangdong Provincial Department of Science and Technology, China (Grant No. 2016A030313738; http://www.gdstc.gov.cn/), and grants from the School of Public Health of Southern Medical University, China (Grant No. GW201612; http://web2.fimmu.com/phatm/).

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

This study was approved by the Institutional Review Board of Nanfang Hospital affiliated to Southern Medical University, and all patients provided written informed consent for the use of surgical samples. Mice transportation, housing, and breeding were conducted according to the recommendations of ‘‘The use of non-human primates in research.’’ The mice were killed by cervical dislocation to prevent suffering. The Southern Medical University Animal Care and Use Committee approved all procedures involving the mice.

Correspondence to Liang Zhou or Zhenhua Ding.

Supplementary information

  1. SUPPLEMENTAL MATERIAL

  2. Supplementary Table 1

  3. Supplementary Table 2

  4. Supplementary Table 3

  5. Supplementary Table 4

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6