Skip to main content
SpringerLink
Log in

Roles of SALL2 in tumorigenesis

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The proteins p150Sal2 (product of SALL2) and p53 share growth arrest and pro-apoptotic functions by independently inducing p21Cip1/Waf1 and BAX, and both proteins are targeted by the human papilloma virus E6 protein, leading to blockage of growth arrest in infected cells. Loss of both p53 and Sall2 in mice causes significantly higher mortality and metastasis rates compared with p53 single mutant mice. Therefore, p150Sal2 seems to have strong potential as a novel cancer biomarker for early diagnosis and risk prediction. Loss of SALL2 expression is observed in many cases of human serous ovarian carcinoma, whereas normal ovarian epithelial cells maintain high levels of the p150Sal2 protein, supporting an important tumor suppressive role for p150Sal2 in the human ovary. In contrast, p150Sal2 is a transcription factor required to convert differentiated glioblastoma cells into stem-like tumor-propagating cells, suggesting that its functional roles are dependent on tissue types and cellular context. The function of p150Sal2 in normal and diseased cells and possible therapeutic approaches are discussed in this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Bandera CA, Takahashi H, Behbakht K, Liu PC, LiVolsi VA, Benjamin I, Morgan MA, King SA, Rubin SC, Boyd J (1997) Deletion mapping of two potential chromosome 14 tumor suppressor gene loci in ovarian carcinoma. Cancer Res 57:513–515

    CAS  PubMed  Google Scholar 

  • Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760

    Article  CAS  PubMed  Google Scholar 

  • Bohm J, Buck A, Borozdin W, Mannan AU, Matysiak-Scholze U, Adham I, Schulz-Schaeffer W, Floss T, Wurst W, Kohlhase J, Barrionuevo F (2008) Sall1, sall2, and sall4 are required for neural tube closure in mice. Am J Pathol 173:1455–1463

    Article  PubMed  PubMed Central  Google Scholar 

  • Chai L (2011) The role of HSAL (SALL) genes in proliferation and differentiation in normal hematopoiesis and leukemogenesis. Transfusion 51(Suppl 4):87S–93S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chai F, Li HY, Wang W, Zhu XJ, Li Y, Wang S, Guo L, Zhang LK, Xiao G (2015) Subcellular quantitative proteomic analysis reveals host proteins involved in human cytomegalovirus infection. Biochim Biophys Acta 1854:967–978

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403

    Article  CAS  PubMed  Google Scholar 

  • Cho HS, Suzuki T, Dohmae N, Hayami S, Unoki M, Yoshimatsu M, Toyokawa G, Takawa M, Chen T, Kurash JK, Field HI, Ponder BA, Nakamura Y, Hamamoto R (2011) Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res 71:655–660

    Article  CAS  PubMed  Google Scholar 

  • Escobar D, Hepp MI, Farkas C, Campos T, Sodir NM, Morales M, Alvarez CI, Swigart L, Evan GI, Gutierrez JL, Nishinakamura R, Castro AF, Pincheira R (2015) Sall2 is required for proapoptotic Noxa expression and genotoxic stress-induced apoptosis by doxorubicin. Cell Death Disord 6:e1816

    Article  CAS  Google Scholar 

  • Farkas C, Martins CP, Escobar D, Hepp MI, Castro AF, Evan G, Gutierrez JL, Warren R, Donner DB, Pincheira R (2013) Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress. PLoS ONE 8:e73817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallagher D, Voronova A, Zander MA, Cancino GI, Bramall A, Krause MP, Abad C, Tekin M, Neilsen PM, Callen DF, Scherer SW, Keller GM, Kaplan DR, Walz K, Miller FD (2015) Ankrd11 is a chromatin regulator involved in autism that is essential for neural development. Dev Cell 32:31–42

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59:675–680

    Article  CAS  PubMed  Google Scholar 

  • Goujon C, Moncorge O, Bauby H, Doyle T, Ward CC, Schaller T, Hue S, Barclay WS, Schulz R, Malim MH (2013) Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 502:559–562

    Article  CAS  PubMed  Google Scholar 

  • Gu H, Li D, Sung CK, Yim H, Troke P, Benjamin T (2011) DNA-binding and regulatory properties of the transcription factor and putative tumor suppressor p150 (Sal2). Biochim Biophys Acta 1809:276–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamouille S, Derynck R (2009) Oncogene and tumour suppressor: the two faces of SnoN. EMBO J 28:3459–3460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee TC, Ziff EB (1999) Mxi1 is a repressor of the c-Myc promoter and reverses activation by USF. J Biol Chem 274:595–606

    Article  CAS  PubMed  Google Scholar 

  • Li D, Dower K, Ma Y, Tian Y, Benjamin TL (2001) A tumor host range selection procedure identifies p150(sal2) as a target of polyoma virus large T antigen. Proc Natl Acad Sci USA 98:14619–14624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li D, Tian Y, Ma Y, Benjamin T (2004) p150(Sal2) is a p53-independent regulator of p21(WAF1/CIP). Mol Cell Biol 24:3885–3893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu H, Adler AS, Segal E, Chang HY (2007) A transcriptional program mediating entry into cellular quiescence. PLoS Genet 3:e91

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu J, Wang L, Yang A, Jiang P, Wang M (2014) Up-regulation of SALL4 associated with poor prognosis in gastric cancer. Hepato-gastroenterology 61:1459–1464

    CAS  Google Scholar 

  • Negrini S, Prada I, D’Alessandro R, Meldolesi J (2013) REST: an oncogene or a tumor suppressor? Trends Cell Biol 23:289–295

    Article  CAS  PubMed  Google Scholar 

  • Parroche P, Touka M, Mansour M, Bouvard V, Thepot A, Accardi R, Carreira C, Roblot GG, Sylla BS, Hasan U, Tommasino M (2011) Human papillomavirus type 16 E6 inhibits p21(WAF1) transcription independently of p53 by inactivating p150(Sal2). Virology 417:443–448

    Article  CAS  PubMed  Google Scholar 

  • Pavlovic J, Zurcher T, Haller O, Staeheli P (1990) Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol 64:3370–3375

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rao F, Xu J, Khan AB, Gadalla MM, Cha JY, Xu R, Tyagi R, Dang Y, Chakraborty A, Snyder SH (2014) Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNA repair and cell death. Proc Natl Acad Sci USA 111:16005–16010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rowland BD, Peeper DS (2006) KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer 6:11–23

    Article  CAS  PubMed  Google Scholar 

  • Sato A, Matsumoto Y, Koide U, Kataoka Y, Yoshida N, Yokota T, Asashima M, Nishinakamura R (2003) Zinc finger protein sall2 is not essential for embryonic and kidney development. Mol Cell Biol 23:62–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2015) Cancer Statistics, 2015. CA Cancer J Clin 65:5–29

  • Sung CK, Yim H (2015) The tumor suppressor protein p150sal2 in carciongenesis. Tumor Biol 36:489–494

    Article  CAS  Google Scholar 

  • Sung CK, Dahl J, Yim H, Rodig S, Benjamin TL (2011) Transcriptional and post-translational regulation of the quiescence factor and putative tumor suppressor p150(Sal2). FASEB J 25:1275–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sung CK, Yim H, Gu H, Li D, Andrews E, Duraisamy S, Li C, Drapkin R, Benjamin T (2012) The polyoma virus large T binding protein p150 is a transcriptional repressor of c-MYC. PLoS ONE 7:e46486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sung CK, Li D, Andrews E, Drapkin R, Benjamin T (2013) Promoter methylation of the SALL2 tumor suppressor gene in ovarian cancers. Mol Oncol 7:419–427

    Article  CAS  PubMed  Google Scholar 

  • Suva ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV, Curry WT, Martuza RL, Rivera MN, Rossetti N, Kasif S, Beik S, Kadri S, Tirosh I, Wortman I, Shalek AK, Rozenblatt-Rosen O, Regev A, Louis DN, Bernstein BE (2014) Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157:580–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanimura N, Saito M, Ebisuya M, Nishida E, Ishikawa F (2013) Stemness-related factor Sall4 interacts with transcription factors Oct-3/4 and Sox2 and occupies Oct-Sox elements in mouse embryonic stem cells. J Biol Chem 288:5027–5038

    Article  CAS  PubMed  Google Scholar 

  • Wang ZG, Zheng H, Gao W, Han J, Cao JZ, Yang Y, Li S, Gao R, Liu H, Pan ZY, Fu SY, Gu FM, Xing H, Ni JS, Yan HL, Ren H, Zhou WP (2016) eIF5B increases ASAP1 expression to promote HCC proliferation and invasion. Oncotarget 7:62327–62339

    PubMed  Google Scholar 

  • Wu Z, Cheng K, Shi L, Li Z, Negi H, Gao G, Kamle S, Li D (2015) Sal-like protein 2 upregulates p16 expression through a proximal promoter element. Cancer Sci 106:253–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang L, Han Y, Suarez Saiz F, Minden MD (2007) A tumor suppressor and oncogene: the WT1 story. Leukemia 21:868–876

    CAS  PubMed  Google Scholar 

  • Yang CM, Chiba T, Brill B, Delis N, von Manstein V, Vafaizadeh V, Oellerich T, Groner B (2015) Expression of the miR-302/367 cluster in glioblastoma cells suppresses tumorigenic gene expression patterns and abolishes transformation related phenotypes. Int J Cancer 137:2296–2309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS, Lou Y, Yang J, Ma Y, Chai L, Ng HH, Lufkin T, Robson P, Lim B (2006) Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 8:1114–1123

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Gao Y, Li P, Shi Z, Guo T, Li F, Han X, Feng Y, Zheng C, Wang Z, Li F, Chen H, Zhou Z, Zhang L, Ji H (2014) VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex. Cell Res 24:331–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zihni C, Mitsopoulos C, Tavares IA, Ridley AJ, Morris JD (2006) Prostate-derived sterile 20-like kinase 2 (PSK2) regulates apoptotic morphology via C-Jun N-terminal kinase and Rho kinase-1. J Biol Chem 281:7317–7323

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Science Foundation (to CKS; NSF CBET-1504174) and the research fund of Hanyang University (HY-2014-N) to HY.

Author information

Authors and Affiliations

  1. Department of Biological and Health Sciences, Texas A&M University-Kingsville, Kingsville, TX, 78363, USA

    Chang K. Sung

  2. Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea

    Hyungshin Yim

Authors
  1. Chang K. Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyungshin Yim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hyungshin Yim.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sung, C.K., Yim, H. Roles of SALL2 in tumorigenesis. Arch. Pharm. Res. 40, 146–151 (2017). https://doi.org/10.1007/s12272-016-0874-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-016-0874-x

Keywords

Search

Navigation