Home SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A
Article
Licensed
Unlicensed Requires Authentication

SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A

  • Weihua Xu , Kanqiu Jiang , Mingjing Shen , Yongyue Qian and Yong Peng EMAIL logo
Published/Copyright: March 14, 2015
Biological Chemistry
From the journal Biological Chemistry Volume 396 Issue 8

Abstract

Lung cancer has been the most prolific cancer in China – as in the rest of the world – with a high death rate and low 5-year survival rate. Previous evidence showed that JMJD2A is over-expressed in human non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues, and that high level of JMJD2A predicts poor overall and disease-free survival. However, the mechanism by which JMJD2A is regulated in human NSCLC is not fully understood. In the present study, we identified that the SIRT2 as an anti-oncogenic protein in NSCLC was down-regulated. JMJD2A as a target of SIRT2 was negatively correlated with SIRT2 level in NSCLC. SIRT2 bound to the promoter region of JMJD2A and negatively regulated JMJD2A expression. In addition, we found that SIRT2 inhibited NSCLC cells proliferation, colony formation and tumor growth in vitro and in vivo in a JMJD2A-dependent manner. In summary, our findings implicate that SIRT2 suppresses non-small cell lung cancer growth through targeting JMJD2A and SIRT2 activator may serve as candidate drug for NSCLC therapy.

Keywords: human non-small cell lung cancer; JMJD2A; SIRT2
Corresponding author: Yong Peng, Department of Cardiothoracic Surgery, Suzhou Municipal Hospital, 26 Daoqian Street, Suzhou 215002, Jiangsu, China, e-mail:
aThese authors contributed equally to this work.

References

Arora, A. and Dey, C.S. (2014). SIRT2 negatively regulates insulin resistance in C2C12 skeletal muscle cells. Biochim. Biophys. Acta Mol. Basis Dis. 1842, 1372–1378.10.1016/j.bbadis.2014.04.027Search in Google Scholar PubMed

Beirowski, B., Gustin, J., Armour, S.M., Yamamoto, H., Viader, A., North, B.J., Michán, S., Baloh, R.H., Golden, J.P., and Schmidt, R.E. (2011). Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling. Proc. Natl. Acad. Sci. USA 108, E952–E961.10.1073/pnas.1104969108Search in Google Scholar PubMed PubMed Central

Berry, W.L., Shin, S., Lightfoot, S.A., and Janknecht, R. (2012). Oncogenic features of the JMJD2A histone demethylase in breast cancer. Int. J. Oncol. 41, 1701–1706.10.3892/ijo.2012.1618Search in Google Scholar PubMed

Carney, D.N. and Hansen, H.H. (2000). Non-small-cell lung cancer – stalemate or progress? N. Engl. J. Med. 343, 1261–1262.10.1056/NEJM200010263431710Search in Google Scholar PubMed

Cheon, M.G., Kim, W., Choi, M., and Kim, J.E. (2015). AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells. Cancer Lett. 356, 637–645.10.1016/j.canlet.2014.10.012Search in Google Scholar PubMed

Das, A., Chai, J.C., Jung, K.H., Das, N.D., Kang, S.C., Lee, Y.S., Seo, H., and Chai, Y.G. (2014). JMJD2A attenuation affects cell cycle and tumourigenic inflammatory gene regulation in lipopolysaccharide stimulated neuroectodermal stem cells. Exp. Cell Res. 328, 361–378.10.1016/j.yexcr.2014.08.029Search in Google Scholar PubMed

Fodor, B.D., Kubicek, S., Yonezawa, M., O’Sullivan, R.J., Sengupta, R., Perez-Burgos, L., Opravil, S., Mechtler, K., Schotta, G., and Jenuwein, T. (2006). JMJD2B antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562.10.1101/gad.388206Search in Google Scholar PubMed PubMed Central

Gal, J., Bang, Y., and Choi, H.J. (2012). SIRT2 interferes with autophagy-mediated degradation of protein aggregates in neuronal cells under proteasome inhibition. Neurochem. Int. 61, 992–1000.10.1016/j.neuint.2012.07.010Search in Google Scholar PubMed

Han, W., Xin, Z., Zhao, Z., Bao, W., Lin, X., Yin, B., Zhao, J., Yuan, J., Qiang, B., and Peng, X. (2013). RNA-binding protein PCBP2 modulates glioma growth by regulating FHL3. J. Clin. Invest. 123, 2103–2118.10.1172/JCI61820Search in Google Scholar PubMed PubMed Central

Hiratsuka, M., Inoue, T., Toda, T., Kimura, N., Shirayoshi, Y., Kamitani, H., Watanabe, T., Ohama, E., Tahimic, C.G., and Kurimasa, A. (2003). Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem. Biophys. Res. Commun. 309, 558–566.10.1016/j.bbrc.2003.08.029Search in Google Scholar PubMed

Hu, C.E., Liu, Y.C., Zhang, H.D., and Huang, G.J. (2014). JMJD2A predicts prognosis and regulates cell growth in human gastric cancer. Biochem. Biophys. Res. Commun. 449, 1–7.10.1016/j.bbrc.2014.04.126Search in Google Scholar PubMed

Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D. (2011). Global cancer statistics. CA Cancer J. Clin. 61, 69–90.10.3322/caac.20107Search in Google Scholar PubMed

Kauffman, E.C., Robinson, B.D., Downes, M.J., Powell, L.G., Lee, M.M., Scherr, D.S., Gudas, L.J., and Mongan, N.P. (2011). Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer. Mol. Carcinog. 50, 931–944.10.1002/mc.20758Search in Google Scholar PubMed PubMed Central

Kim, H.S., Vassilopoulos, A., Wang, R.H., Lahusen, T., Xiao, Z., Xu, X., Li, C., Veenstra, T.D., Li, B., and Yu, H. (2011). SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20, 487–499.10.1016/j.ccr.2011.09.004Search in Google Scholar PubMed PubMed Central

Kogure, M., Takawa, M., Cho, H.S., Toyokawa, G., Hayashi, K., Tsunoda, T., Kobayashi, T., Daigo, Y., Sugiyama, M., and Atomi, Y. (2013). Deregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G1S transition. Cancer Lett. 336, 76–84.10.1016/j.canlet.2013.04.009Search in Google Scholar PubMed

Kooistra, S.M. and Helin, K. (2012). Molecular mechanisms and potential functions of histone demethylases. Nat. Rev. Mol. Cell Biol. 13, 297–311.10.1038/nrm3327Search in Google Scholar PubMed

Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128, 693–705.10.1016/j.cell.2007.02.005Search in Google Scholar PubMed

Kubota, S., Fukumoto, Y., Aoyama, K., Ishibashi, K., Yuki, R., Morinaga, T., Honda, T., Yamaguchi, N., Kuga, T., Tomonaga, T., et al. (2013). Phosphorylation of KRAB-associated protein 1 (KAP1) at Tyr-449, Tyr-458, and Tyr-517 by nuclear tyrosine kinases inhibits the association of KAP1 and heterochromatin protein 1α (HP1α) with heterochromatin. J. Biol. Chem. 288, 17871–17883.10.1074/jbc.M112.437756Search in Google Scholar PubMed PubMed Central

Kwon, D.W. and Ahn, S.H. (2011). Role of yeast JmjC-domain containing histone demethylases in actively transcribed regions. Biochem. Biophys. Res. Commun. 410, 614–619.10.1016/j.bbrc.2011.06.039Search in Google Scholar PubMed

Langevin, S.M., Kratzke, R.A., and Kelsey, K.T. (2015). Epigenetics of lung cancer. Transl. Res. 165, 74–90.10.1016/j.trsl.2014.03.001Search in Google Scholar PubMed PubMed Central

Lee, A.S., Jung, Y.J., Kim, D., Nguyen-Thanh, T., Kang, K.P., Lee, S., Park, S.K., and Kim, W. (2014). SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages. Biochem. Biophys. Res. Commun. 450, 1363–1369.10.1016/j.bbrc.2014.06.135Search in Google Scholar PubMed

Li, Y., Dai, D., Lu, Q., Fei, M., Li, M., and Wu, X. (2013a). Sirt2 suppresses glioma cell growth through targeting NF-κB–miR-21 axis. Biochem. Biophys. Res. Commun. 441, 661–667.10.1016/j.bbrc.2013.10.077Search in Google Scholar PubMed

Li, Z., Xie, Q.R., Chen, Z., Lu, S., and Xia, W. (2013b). Regulation of SIRT2 levels for human non-small cell lung cancer therapy. Lung Cancer 82, 9–15.10.1016/j.lungcan.2013.05.013Search in Google Scholar PubMed

Mallette, F.A. and Richard, S. (2012). JMJD2A promotes cellular transformation by blocking cellular senescence through transcriptional repression of the tumor suppressor CHD5. Cell Rep. 2, 1233–1243.10.1016/j.celrep.2012.09.033Search in Google Scholar PubMed

Mostafa, A.A. and Morris, D.G. (2014). Immunotherapy for lung cancer: has it finally arrived? Front. Oncol. 4, 288.10.3389/fonc.2014.00288Search in Google Scholar PubMed PubMed Central

Narayan, N., Lee, I.H., Borenstein, R., Sun, J., Wong, R., Tong, G., Fergusson, M.M., Liu, J., Rovira, I.I., and Cheng, H.L. (2012). The NAD-dependent deacetylase SIRT2 is required for programmed necrosis. Nature 492, 199–204.10.1038/nature11700Search in Google Scholar PubMed

North, B.J. and Verdin, E. (2007). Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS One 2, e784.10.1371/journal.pone.0000784Search in Google Scholar PubMed PubMed Central

Peck, B., Chen, C.Y., Ho, K.K., Di Fruscia, P., Myatt, S.S., Coombes, R.C., Fuchter, M.J., Hsiao, C.D., and Lam, E.W. (2010). SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol. Cancer Ther. 9, 844–855.10.1158/1535-7163.MCT-09-0971Search in Google Scholar PubMed

Risch, A. and Plass, C. (2008). Lung cancer epigenetics and genetics, Int. J. Cancer 123, 1–7.Search in Google Scholar

Shin, S. and Janknecht, R. (2007). Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D. Biochem. Biophys. Res. Commun. 359, 742–746.10.1016/j.bbrc.2007.05.179Search in Google Scholar PubMed

Suematsu, T., Li, Y., Kojima, H., Nakajima, K., Oshimura, M., and Inoue T. (2014). Deacetylation of the mitotic checkpoint protein BubR1 at lysine 250 by SIRT2 and subsequent effects on BubR1 degradation during the prometaphase/anaphase transition. Biochem. Biophys. Res. Commun. 453, 588–594.10.1016/j.bbrc.2014.09.128Search in Google Scholar PubMed

Wang, J., Zhang, M., Zhang, Y., Kou, Z., Han, Z., Chen, D.Y., Sun, Q.Y., and Gao, S. (2010). The histone demethylase JMJD2C is stage-specifically expressed in preimplantation mouse embryos and is required for embryonic development. Biol. Reprod. 82, 105–111.10.1095/biolreprod.109.078055Search in Google Scholar PubMed

Young, L.C. and Hendzel, M.J. (2012). The oncogenic potential of Jumonji D2 (JMJD2/KDM4) histone demethylase overexpression. Biochem. Cell Biol. 91, 369–377.10.1139/bcb-2012-0054Search in Google Scholar PubMed

Zhao, Y., Wang, S., Aunan, K., Martin Seip, H., and Hao, J. (2006). Air pollution and lung cancer risks in China – a meta-analysis. Sci. Total. Environ. 366, 500–513.10.1016/j.scitotenv.2005.10.010Search in Google Scholar PubMed

Supplemental Material

The online version of this article (DOI: 10.1515/hsz-2014-0284) offers supplementary material, available to authorized users.

Received: 2014-12-1
Accepted: 2015-2-12
Published Online: 2015-3-14
Published in Print: 2015-8-1

©2015 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Ras activation revisited: role of GEF and GAP systems
  4. When core competence is not enough: functional interplay of the DEAD-box helicase core with ancillary domains and auxiliary factors in RNA binding and unwinding
  5. Cathepsin S: therapeutic, diagnostic, and prognostic potential
  6. Minireview
  7. Overview of the roles of Sox2 in stem cell and development
  8. Research Articles/Short Communications
  9. Genes and Nucleic Acids
  10. Transcriptional and translational mechanisms contribute to regulate the expression of Discs Large 1 protein during different biological processes
  11. Membranes, Lipids, Glycobiology
  12. Rapid transfer of overexpressed integral membrane protein from the host membrane into soluble lipid nanodiscs without previous purification
  13. Molecular Medicine
  14. Characterization of a new dual-targeting fully human antibody with potent antitumor activity against nasopharyngeal carcinoma
  15. Cell Biology and Signaling
  16. Lithium chloride improves the efficiency of induced pluripotent stem cell-derived neurospheres
  17. SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A
  18. Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism
https://doi.org/10.1515/hsz-2014-0284
Keywords for this article
human non-small cell lung cancer; JMJD2A; SIRT2

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Ras activation revisited: role of GEF and GAP systems
  4. When core competence is not enough: functional interplay of the DEAD-box helicase core with ancillary domains and auxiliary factors in RNA binding and unwinding
  5. Cathepsin S: therapeutic, diagnostic, and prognostic potential
  6. Minireview
  7. Overview of the roles of Sox2 in stem cell and development
  8. Research Articles/Short Communications
  9. Genes and Nucleic Acids
  10. Transcriptional and translational mechanisms contribute to regulate the expression of Discs Large 1 protein during different biological processes
  11. Membranes, Lipids, Glycobiology
  12. Rapid transfer of overexpressed integral membrane protein from the host membrane into soluble lipid nanodiscs without previous purification
  13. Molecular Medicine
  14. Characterization of a new dual-targeting fully human antibody with potent antitumor activity against nasopharyngeal carcinoma
  15. Cell Biology and Signaling
  16. Lithium chloride improves the efficiency of induced pluripotent stem cell-derived neurospheres
  17. SIRT2 suppresses non-small cell lung cancer growth by targeting JMJD2A
  18. Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 8.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2014-0284/html?lang=en
Scroll to top button