Skip to main content

Advertisement

SpringerLink
Log in

NSD1 promotes esophageal cancer tumorigenesis via HIF1α signaling

  • Research
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Abstract

Unlike angiogenesis in normal tissues, tumor angiogenesis is typically dysregulated, during which the HIF1/VEGFA signaling pathway plays a pivotal role. Solid tumors generate immature vessels, which promote tumor progression and treatment resistance. NSD1 can di-methylate histone 3 lysine 36 and regulate transcription factors binding to the promoters of various genes. However, the role of NSD1 in tumorigenesis remains elusive. Here, we evaluated the relationship between NSD1 signaling and HIF1 signaling. It was found that NSD1 transcriptionally regulates HIF1α expression by recruiting STAT3 molecule into the HIF1α promoter. In vivo xenograft experiments further confirmed that HIF1α and STAT3 maintenance is essential for NSD1-mediated tumor progression and angiogenesis. Therefore, the NSD1/STAT3/HIF1α signaling pathway may be a novel and effective treatment target for ESCA.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

References

  • Bianco-Miotto T, Chiam K, Buchanan G, Jindal S, Day TK, Thomas M, et al. Global levels of specific histone modifications and an epigenetic gene signature predict prostate cancer progression and development. Cancer Epidemiol Biomark Prev. 2010;19(10):2611–22.

    Article  CAS  Google Scholar 

  • Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.

    Article  Google Scholar 

  • Choufani S, Cytrynbaum C, Chung BH, Turinsky AL, Grafodatskaya D, Chen YA, et al. NSD1 mutations generate a genome-wide DNA methylation signature. Nat Commun. 2015;6:10207.

    Article  CAS  PubMed  Google Scholar 

  • Chu G, Li Y, Dong X, Liu J, Zhao Y. Role of NSD1 in H2O2-induced GSTM3 suppression. Cell Signal. 2014;26(12):2757–64.

    Article  CAS  PubMed  Google Scholar 

  • de Heer EC, Jalving M, Harris AL. HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest. 2020;130(10):5074–87.

    Article  PubMed  PubMed Central  Google Scholar 

  • De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17(8):457–74.

    Article  PubMed  Google Scholar 

  • Denko NC. Hypoxia, HIF1 and glucose__metabolism in the solid tumour. Nat Rev Cancer. 2008;8(9):705–13.

    Article  CAS  PubMed  Google Scholar 

  • Deshpande AJ, Deshpande A, Sinha AU, Chen L, Chang J, Cihan A, et al. AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell. 2014;26(6):896–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Enzinger PC, Mayer RJ. Esophageal Cancer. N Engl J Med. 2003;349:2241–52.

    Article  CAS  PubMed  Google Scholar 

  • Eswarappa SM, Fox PL. Antiangiogenic VEGF-Ax: a new participant in tumor angiogenesis. Cancer Res. 2015;75(14):2765–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giaccia A, Siim BG, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov. 2003;2(10):803–11.

    Article  CAS  PubMed  Google Scholar 

  • He F, Xiao H, Cai Y, Zhang N. ATF5 and HIF1alpha cooperatively activate HIF1 signaling pathway in esophageal cancer. Cell Commun Signal. 2021;19(1):53.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Pratcorona M, Abbas S, Kuipers JE, et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood. 2011;118(13):3645–56.

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Howard CA, Zari S, Cho HJ, Shukla S, Li H, et al. Covalent inhibition of NSD1 histone methyltransferase. Nat Chem Biol. 2020;16(12):1403–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jimenez-Valerio G, Casanovas O. Angiogenesis and metabolism: entwined for therapy resistance. Trends Cancer. 2017;3(1):10–8.

    Article  CAS  PubMed  Google Scholar 

  • Kasper S, Schuler M. Targeted therapies in gastroesophageal cancer. Eur J Cancer. 2014;50(7):1247–58.

    Article  CAS  PubMed  Google Scholar 

  • Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129(3):465–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morera L, Lubbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics. 2016;8:57.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ostronoff F, Othus M, Gerbing RB, Loken MR, Raimondi SC, Hirsch BA, et al. NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. Blood. 2014;124(15):2400–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pawlus MR, Wang L, Hu CJ. STAT3 and HIF1alpha cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells. Oncogene. 2014;33(13):1670–9.

    Article  CAS  PubMed  Google Scholar 

  • Qiao Q, Li Y, Chen Z, Wang M, Reinberg D, Xu RM. The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. J Biol Chem. 2011;286(10):8361–8.

    Article  CAS  PubMed  Google Scholar 

  • Rustgi AK, El-Serag HB. Esophageal carcinoma. N Engl J Med. 2014;371(26):2499–509.

    Article  PubMed  Google Scholar 

  • Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32.

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda). 2004;19:176–82.

    CAS  PubMed  Google Scholar 

  • Semenza GL. Hypoxia-Inducible Factor 1 (HIF-1) Pathway. Sci STKE. 2007;407:cm8.

    Google Scholar 

  • Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29(5):625–34.

    Article  CAS  PubMed  Google Scholar 

  • Sharp FR, Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci. 2004;5(6):437–48.

    Article  CAS  PubMed  Google Scholar 

  • Smyth EC, Lagergren J, Fitzgerald RC, Lordick F, Shah MA, Lagergren P, et al. Oesophageal cancer. Nat Rev Dis Primers. 2017;3:17048.

    Article  PubMed  PubMed Central  Google Scholar 

  • Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 2000;60(2):203–12.

    CAS  PubMed  Google Scholar 

  • Wagner EJ, Carpenter PB. Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol. 2012;13(2):115–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang GG, Cai L, Pasillas MP, Kamps MP. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol. 2007;9(7):804–12.

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Byfield G, Jiang Y, Smith GW, McCloskey M, Hartnett ME. VEGF-mediated STAT3 activation inhibits retinal vascularization by down-regulating local erythropoietin expression. Am J Pathol. 2012;180(3):1243–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17(11):1359–70.

    Article  CAS  PubMed  Google Scholar 

  • You L, Wu W, Wang X, Fang L, Adam V, Nepovimova E, et al. The role of hypoxia-inducible factor 1 in tumor immune evasion. Med Res Rev. 2020.

  • Zanotelli MR, Reinhart-King CA. Mechanical forces in tumor angiogenesis. Adv Exp Med Biol. 2018;1092:91–112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang S, Zhang F, Chen Q, Wan C, Xiong J, Xu J. CRISPR/Cas9-mediated knockout of NSD1 suppresses the hepatocellular carcinoma development via the NSD1/H3/Wnt10b signaling pathway. J Exp Clin Cancer Res. 2019;38(1):467.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study has been supported by the double first class construction project of Tongji Medical College of Huazhong University of science and technology—research clinician funding scheme, 3011540027 and 5001540077, and Natural Science Foundation of Hubei Province, 2016CFB550.

Author information

Authors and Affiliations

  1. Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China

    Feng He, Hang Xiao, Yixin Cai & Ni Zhang

Authors
  1. Feng He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hang Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yixin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ni Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HF mainly performed the experiment. HF, XH, and CY helped with cell culture, solution preparation, reagents ordering, and in vivo experiments. All authors contributed to collection and grading of clinical samples. ZN provided important comments and opinions for the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Ni Zhang.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Huazhong University of Science and Technology Ethics Committee. All clinic samples were obtained from ESCA patients, and the written informed consent of all patients was received.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Supplementary Figure 1

NSD1 acted as an oncogene in esophageal cancer. a–d Representative images (scale = 200 um) from transwell assays (a, c) and wound healing assays (b, d). e Illustration of colony formation assays. f Representative image of the IHC assay for subcutaneous xenograft tumors, scale = 200 μm. g Statistical analyses for microvessel density of subcutaneous xenograft tumors; **p < 0.05 (PNG 6040 kb)

High Resolution Image (TIF 22889 kb)

Supplementary Figure 2

NSD1 regulated the HIF1/VEGFA signaling pathway. a Relationship between VEGFA and NSD1 expression in esophageal cancer, based on the TCGA database. b, c Immunoblots showing protein expression of cells ectopically expressing vector or NSD1 (b) or NSD1 R1984Q (c). d Immunoblots showing protein expression of cells ectopically expressing shnc or shNSD1. e, f Expression levels of VEGFA in conditional media (CM) of cells stably expressing vector or NSD1 in normoxic (e) and hypoxic (f) environments, as revealed by ELISA; **p < 0.05. g Proliferation activities of HUVECs cultured in CM of cells ectopically expressing vector or NSD1 in normoxia, as revealed by CCK8 assays; **p < 0.05. h Proliferation activities of HUVECs cultured in CM of cells ectopically expressing shnc or shNSD1 under normoxia, as revealed by CCK8 assays; **p < 0.05 (PNG 904 kb)

High Resolution Image (TIF 3527 kb)

Supplementary Figure 3

NSD1 regulated tumor angiogenesis in vitro. a, b Representative images of tube formation assays for HUVECs cultured in CM from cells ectopically expressing shnc or shNSD1 under normoxic (a) and hypoxic (b) conditions, scale = 200 μm. c, d Representative images of trans-well assays for HUVECs cultured in CM of cells ectopically expressing shnc or shNSD1 under normoxia (c) and hypoxia (d) conditions, scale = 200 μm (PNG 3376 kb)

High Resolution Image (TIF 14147 kb)

Supplementary Figure 4

STAT3 acted as a co-activator of NSD1-mediated tumor process. a GSEA analysis of the GSE100942 dataset. b Immunoblots showing the expression levels of indicated proteins in cells expressing shnc or shNSD1. c Immunoblots demonstrating successful construction of cells expressing shnc or shSTAT3. d Representative IHC assay image of subcutaneous xenograft tumors, scale = 200 μm. e Immunoblots showing successful construction of indicated cells. f representative tumor images; scale = 1 cm. g Immunoblots of subcutaneous xenograft tumors showing expression levels of indicated proteins (PNG 2711 kb)

High Resolution Image (TIF 10537 kb)

Supplementary Table 1

(DOCX 20 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, F., Xiao, H., Cai, Y. et al. NSD1 promotes esophageal cancer tumorigenesis via HIF1α signaling. Cell Biol Toxicol 39, 1835–1850 (2023). https://doi.org/10.1007/s10565-022-09786-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-022-09786-2

Keywords

Search

Navigation