Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

SALL4 promotes glycolysis and chromatin remodeling via modulating HP1α-Glut1 pathway

Oncogene volume 36, pages 6472–6479 (2017)Cite this article

Subjects

Abstract

SALL4 has recently been identified to promote chemo-resistance in multiple types of cancer, but the underlying mechanism remains to be fully established. Open chromatin structure is important for DNA damage response (DDR) and DNA repair. Here, we demonstrate that SALL4 promotes open chromatin by destabilizing heterochromatin protein 1α (HP1α) by recruiting ubiquitin E3 ligase CUL4B to HP1α. The silencing of SALL4 in cancer cells decreased the expression levels of Glut1 and inhibited glycolysis in cancer cells. The upregulation of HP1α in human cancer cells suppressed open chromatin, glycolysis and Glut1 expression levels. Therefore, SALL4 promotes the expression of Glut1 and open chromatin through a HP1α-dependent mechanism. Impaired DDR in SALL4-deficient human cancer cells can be rescued by the restored expression of Glut1, indicating the importance of HP1α-Glut1 axis in SALL4-mediated DDR. These findings demonstrate that SALL4 could induce drug resistance by enhancing DDR and DNA repair through promoting glycolysis and subsequent chromatin remodeling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.

    Article  CAS  Google Scholar 

  2. Kim J, Nakasaki M, Todorova D, Lake B, Yuan CY, Jamora C et al. p53 Induces skin aging by depleting Blimp1+ sebaceous gland cells. Cell Death Dis 2014; 5: e1141.

    Article  CAS  Google Scholar 

  3. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008; 40: 499–507.

    Article  CAS  Google Scholar 

  4. Boumahdi S, Driessens G, Lapouge G, Rorive S, Nassar D, Le Mercier M et al. SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature 2014; 511: 246–250.

    Article  CAS  Google Scholar 

  5. Lu X, Mazur SJ, Lin T, Appella E, Xu Y . The pluripotency factor nanog promotes breast cancer tumorigenesis and metastasis. Oncogene 2014; 33: 2655–2664.

    Article  CAS  Google Scholar 

  6. Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res 2010; 70: 10433–10444.

    Article  CAS  Google Scholar 

  7. Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS et al. Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 2006; 8: 1114–1123.

    Article  CAS  Google Scholar 

  8. Sakaki-Yumoto M, Kobayashi C, Sato A, Fujimura S, Matsumoto Y, Takasato M et al. The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development. Development 2006; 133: 3005–3013.

    Article  CAS  Google Scholar 

  9. Kohlhase J, Heinrich M, Liebers M, Frohlich Archangelo L, Reardon W, Kispert A . Cloning and expression analysis of SALL4, the murine homologue of the gene mutated in Okihiro syndrome. Cytogenet Genome Res 2002; 98: 274–277.

    Article  CAS  Google Scholar 

  10. Miettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W et al. SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases. Am J Surg Pathol 2014; 38: 410–420.

    Article  Google Scholar 

  11. Chen YY, Li ZZ, Ye YY, Xu F, Niu RJ, Zhang HC et al. Knockdown of SALL4 inhibits the proliferation and reverses the resistance of MCF-7/ADR cells to doxorubicin hydrochloride. BMC Mol Biol 2016; 17: 6.

    Article  Google Scholar 

  12. Liu L, Zhang J, Yang X, Fang C, Xu H, Xi X . SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer through the Regulation of c-Myc in Endometrial Cancer. PLoS One 2015; 10: e0138515.

    Article  Google Scholar 

  13. Li A, Jiao Y, Yong KJ, Wang F, Gao C, Yan B et al. SALL4 is a new target in endometrial cancer. Oncogene 2015; 34: 63–72.

    Article  CAS  Google Scholar 

  14. Yang M, Xie X, Ding Y . SALL4 is a marker of poor prognosis in serous ovarian carcinoma promoting invasion and metastasis. Oncol Rep 2016; 35: 1796–1806.

    Article  CAS  Google Scholar 

  15. Forghanifard MM, Moghbeli M, Raeisossadati R, Tavassoli A, Mallak AJ, Boroumand-Noughabi S et al. Role of SALL4 in the progression and metastasis of colorectal cancer. J Biomed Sci 2013; 20: 6.

    Article  CAS  Google Scholar 

  16. Zhang L, Xu Z, Xu X, Zhang B, Wu H, Wang M et al. SALL4, a novel marker for human gastric carcinogenesis and metastasis. Oncogene 2014; 33: 5491–5500.

    Article  CAS  Google Scholar 

  17. Yanagihara N, Kobayashi D, Kuribayashi K, Tanaka M, Hasegawa T, Watanabe N . Significance of SALL4 as a drugresistant factor in lung cancer. Int J Oncol 2015; 46: 1527–1534.

    Article  CAS  Google Scholar 

  18. Yong KJ, Chai L, Tenen DG . Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N Engl J Med 2013; 369: 1171–1172.

    CAS  PubMed  Google Scholar 

  19. Cheng J, Gao J, Shuai X, Tao K . Oncogenic protein SALL4 and ZNF217 as prognostic indicators in solid cancers: a metaanalysis of individual studies. Oncotarget 2016; 7: 24314–24325.

    PubMed  PubMed Central  Google Scholar 

  20. Han SX, Wang JL, Guo XJ, He CC, Ying X, Ma JL et al. Serum SALL4 is a novel prognosis biomarker with tumor recurrence and poor survival of patients in hepatocellular carcinoma. J Immunol Res 2014; 2014: 262385.

    PubMed  PubMed Central  Google Scholar 

  21. Bleau AM, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW et al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 2009; 4: 226–235.

    Article  CAS  Google Scholar 

  22. Oikawa T, Kamiya A, Zeniya M, Chikada H, Hyuck AD, Yamazaki Y et al. Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers. Hepatology 2013; 57: 1469–1483.

    Article  CAS  Google Scholar 

  23. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N et al. Drug resistance in cancer: an overview. Cancers 2014; 6: 1769–1792.

    Article  CAS  Google Scholar 

  24. Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355: 983–991.

    Article  CAS  Google Scholar 

  25. Bouwman P, Jonkers J . The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer 2012; 12: 587–598.

    Article  CAS  Google Scholar 

  26. Xiong J, Todorova D, Su NY, Kim J, Lee PJ, Shen Z et al. Stemness factor Sall4 is required for DNA damage response in embryonic stem cells. J Cell Biol 2015; 208: 513–520.

    Article  CAS  Google Scholar 

  27. Shiloh Y, Ziv Y . The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 2013; 14: 197–210.

    Article  CAS  Google Scholar 

  28. Kim YC, Gerlitz G, Furusawa T, Catez F, Nussenzweig A, Oh KS et al. Activation of ATM depends on chromatin interactions occurring before induction of DNA damage. Nat Cell Biol 2009; 11: 92–96.

    Article  CAS  Google Scholar 

  29. Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat Cell Biol 2006; 8: 870–876.

    Article  CAS  Google Scholar 

  30. Murga M, Jaco I, Fan Y, Soria R, Martinez-Pastor B, Cuadrado M et al. Global chromatin compaction limits the strength of the DNA damage response. J Cell Biol 2007; 178: 1101–1108.

    Article  CAS  Google Scholar 

  31. Kim JA, Kruhlak M, Dotiwala F, Nussenzweig A, Haber JE . Heterochromatin is refractory to gamma-H2AX modification in yeast and mammals. J Cell Biol 2007; 178: 209–218.

    Article  CAS  Google Scholar 

  32. Faucher D, Wellinger RJ . Methylated H3K4, a transcription-associated histone modification, is involved in the DNA damage response pathway. PLoS Genet 2010; 6: e1001082.

    Article  Google Scholar 

  33. Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Lobrich M et al. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell 2008; 31: 167–177.

    Article  CAS  Google Scholar 

  34. Petroski MD, Deshaies RJ . Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 2005; 6: 9–20.

    Article  CAS  Google Scholar 

  35. Sulli G, Di Micco R, d'Adda di Fagagna F . Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer. Nat Rev Cancer 2012; 12: 709–720.

    Article  CAS  Google Scholar 

  36. Liu XS, Little JB, Yuan ZM . Glycolytic metabolism influences global chromatin structure. Oncotarget 2015; 6: 4214–4225.

    PubMed  PubMed Central  Google Scholar 

  37. Latham T, Mackay L, Sproul D, Karim M, Culley J, Harrison DJ et al. Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression. Nucleic Acids Res 2012; 40: 4794–4803.

    Article  CAS  Google Scholar 

  38. Young CD, Lewis AS, Rudolph MC, Ruehle MD, Jackman MR, Yun UJ et al. Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo. PLoS One 2011; 6: e23205.

    Article  CAS  Google Scholar 

  39. Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 2011; 145: 732–744.

    Article  CAS  Google Scholar 

  40. Zhong L, D'Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 2010; 140: 280–293.

    Article  CAS  Google Scholar 

  41. Lu J, Jeong HW, Kong N, Yang Y, Carroll J, Luo HR et al. Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. PLoS One 2009; 4: e5577.

    Article  Google Scholar 

  42. Molina-Serrano D, Kirmizis A . Beyond the histone tail: acetylation at the nucleosome dyad commands transcription. Nucleus 2013; 4: 343–348.

    Article  Google Scholar 

  43. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C . Clonogenic assay of cells in vitro. Nat Protoc 2006; 1: 2315–2319.

    Article  CAS  Google Scholar 

  44. Abmayr SM, Yao T, Parmely T, Workman JL . Preparation of nuclear and cytoplasmic extracts from mammalian cells. Curr Protoc Mol Biol 2006; Chapter 12: Unit 12 11.

Download references

Acknowledgements

We thank Michael Qiu for technical support. This study is supported by the National Natural Science Foundation of China (No. 815300045, 81373166, 81430032), a grant from the National High-tech R&D Program (863 Program No. 2015AA020310), Guangdong Provincial Key Laboratory of Tumor Immunotherapy and Guangzhou Key Laboratory of Tumor Immunology Research, South Wisdom Valley Innovative Research Team Program (2014) No. 365, Major basic research developmental project of the Natural Science Foundation of Guangdong Province, Shenzhen Municipal Science and Technology Innovation Council (20140405201035), and grants from California Institute for Regenerative Medicine (TR3-05559, RT3-07899).

Author contributions

J.K. with the help of S.X. and L.Y. performed experiments. J.K, X.F. and Y.X. planned the experiments and interpreted the data. X.F. and Y.X. provided the administrative support. J.K. and Y.X. were responsible for the initial draft of the manuscript, whereas other authors contributed to the final edited versions.

Author information

Authors and Affiliations

  1. Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    J Kim, S Xu, L Yu & Y Xu

  2. Division of Biological Sciences, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA, USA,

    J Kim, L Xiong & Y Xu

  3. The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China

    L Yu & X Fu

Authors
  1. J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Xu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J., Xu, S., Xiong, L. et al. SALL4 promotes glycolysis and chromatin remodeling via modulating HP1α-Glut1 pathway. Oncogene 36, 6472–6479 (2017). https://doi.org/10.1038/onc.2017.265

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.265

This article is cited by

Search

Advanced search

Quick links