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July Newsletter: SUMO Wrestling: All About Balance

In mammalian cells, the small ubiquitin-like modifier (SUMO) family contains four isoforms (SUMO1, SUMO2, SUMO3, and SUMO4). SUMO2 and SUMO3 are almost identical, with only a difference in three amino acid residues. SUMO1 shares 48% identity with SUMO2/31. SUMO4 is about 85% identical to SUMO2/3, but it is unclear whether SUMO4 can be conjugated to substrates2. Similar to ubiquitination, SUMOylation requires a three enzymes system (E1, E2, and E3) to conjugate SUMO covalently to target substrates. Briefly, SUMO is first activated by the SUMO E1 activating heterodimeric enzyme SAE1/SAE2 by adenylation in an ATP-dependent reaction. The activated SUMO is then transferred to the SUMO E2 conjugating enzyme UBC9 and finally conjugated to a target protein by a SUMO E3 ligase (e.g., PIAS family members, Ran binding protein 2). The covalently linked SUMO can be removed by sentrin-specific proteases (SENPs), a process known as deSUMOylation3 (Fig. 1). SUMOylation is an essential post-translational modification (PTM) that regulates the activity, subcellular localization, stability, and functions of target proteins and thereby modulates almost all major cellular pathways4. Therefore, it is not surprising that many diseases are associated with dysregulation of SUMOylation. In this newsletter, the roles of SUMOylation/deSUMOylation in cancer are discussed.

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 SUMOylation in Cancer Development 

Cancer occurs when cells grow abnormally. Many regulatory proteins involved in cell cycle progression are tightly regulated by PTMs, and SUMOylation has been identified as one of the major players in cell cycle progression and cancer regulation5. Overexpression of components of the SUMO conjugation pathway supports tumor growth. For example, the oncoprotein Myc activates the transcription of SUMO-activating enzyme E1 (SAE1)6. SAE1 and its partner SAE2 are important in supporting Myc-driven tumorigenesis. Depletion of SAE2 greatly reduces levels of SUMO1- or SUMO2/3- modified proteins, leading to decreases in Myc-dependent breast cancer growth and clonogenicity7. Other studies have reported that the SUMO E2-conjugating enzyme UBC9 is important in early stages of cancer development8 and is overexpressed in lung, primary colon, and prostate cancers. Interestingly, UBC9 levels are downregulated in metastatic breast, lung, and prostate cancers compared with corresponding normal tissues and primary tumors9. In viral (HPV)-mediated head and neck tumorigenesis, UBC9 levels are upregulated through autophagic processes8. In astrocytic brain tumors, upregulation of UBC9, SUMO1-, and SUMO2/3-conjugated proteins promotes tumor growth. Blocking SUMO1-3 conjugation in glioblastoma cells impairs DNA synthesis, cell proliferation, and clonogenicity due to DNA double-strand damage and G2/M cell cycle arrest10. Further, the SUMO E3 ligase PIAS1 is involved in tumorigenesis11. PIAS1 is amplified in prostate cancer where it promotes cell proliferation by suppressing p2112. PIAS1 is highly expressed in Myc-driven B cell lymphomas. It stabilizes Myc in a SUMOylation-dependent manner. PISA1 also promotes Myc phosphorylation at S62, leading to stabilization and upregulation of Myc and therefore its transcriptional activity13.

July18Diagram

Figure 1. An outline of SUMOylation and deSUMOylation processes.

 DeSUMOylation in Cancer Development 

DeSUMOylation by SENPs maintains SUMO homeostasis in cells. However, abnormal activity in deSUMOylation also promotes tumorigenesis14. Overexpression of SENP1 is associated with prostate cancer development. Analysis from prostate cancer specimens also reveals that SENP1 expression directly correlates with prostate cancer aggressiveness and recurrence15. SENP1 is upregulated in prostate cancer cells treated with androgen and/or interleukin-6. Upregulation of SENP1 enhances androgen-dependent transcription and c-Jun-dependent transcription; both are important for prostate cancer development16. Interestingly, blocking SENP2 by siRNA enhances hepatocellular carcinoma growth through increased b-catenin stability17. Upregulation of SENP3 enhances epithelial ovarian cancer progression, possibly by inhibiting p53 transcriptional activity and the expression of p2118. Overexpression of SENP3 is associated with the differentiation of oral squamous cell carcinoma19. Upregulation of SENP5 promotes growth in osteosarcoma cells20 and enhances tumorigenesis in hepatocellular carcinoma21. SENP6 is overexpressed in hepatocellular carcinoma tissues. Silencing of SENP6 by shRNA induces growth inhibition and radio-sensitization in hepatocellular carcinoma cell lines22. In breast epithelia, overexpression of the long SENP7 splice variant promotes breast epithelial-mesenchymal transition23.

 Targeting SUMOylation Pathways in Cancer 

SUMOylation pathway has become a potential therapeutic target in cancer. A small molecular STE inhibits SUMO E1-activating enzyme activity and therefore impairs SUMOylation and inhibits lung cancer cell growth. This is particularly important in Myc-driven cancer since its survival is highly dependent on SUMO E1 activity24. Another study has reported that ginkgolic acid binds directly to SUMO E1 and inhibits SUMOylation. Ginkgolic acid treatment inhibits the growth of NOTCH1-driven breast epithelial cells, suggesting a potential effect of ginkgolic acid treatment in NOTCH1-driven breast cancer25. Several chemotherapeutic drugs used in the treatment of acute myeloid leukemia induce the formation of reactive oxygen species, leading to the inhibition of interaction between SUMO E1-activating enzyme and SUMO E2-conjugating enzyme and subsequent reduction in tumor growth26. Arsenic trioxide, an ancient drug used in traditional Chinese medicine, has been shown to promote SUMOylation and subsequent degradation of the PML and PML-RARa, a fusion oncoprotein that drives the development of acute promyelocytic leukemia27.   

 Summary 

PTMs such as acetylation, phosphorylation, ubiquitination, and SUMOylation regulate protein structure, subcellular localization, and activity in all major cellular pathways. Many studies have shown that various human diseases, including cancer, heart failure, neurodegeneration, and brian ischemia/stroke are associated with dysregulation in SUMOylation3. However, there are still unexplored areas regarding how SUMOylation/deSUMOylation interaction (i.e., cross-talk) with other PTMs contributes to pathological conditions. Cytoskeleton offers several Signal-SeekerTM PTM Detection Kits to assist scientists in the identification and evaluation of endogenous levels of PTMs-modified proteins.     

 Related Products & Resources  

Signal Seeker™ Kits    

New Signal-Seeker™ Acetyl-Lysine Detection Kit (30 assay) (Cat. # BK163)

New Signal-Seeker™ Acetyl-Lysine Detection Kit (10 assay) (Cat. # BK163-S)

Signal-Seeker™ Phosphotyrosine Detection Kit (30 assay) (Cat. # BK160)

Signal-Seeker™ Phosphotyrosine Detection Kit (10 assay) (Cat. # BK160-S)

Signal-Seeker™ Ubiquitination Detection Kit (30 assay) (Cat. # BK161)

Signal-Seeker™ Ubiquitination Detection Kit (10 assay) (Cat. # BK161-S)

Signal-Seeker™ SUMOylation 2/3 Detection Kit (30 assay) (Cat. # BK162)

Signal-Seeker™ SUMOylation 2/3 Detection Kit (10 assay) (Cat. # BK162-S)

PTM Antibodies, Beads, Etc   

New Acetyl-Lysine Antibody Mouse Monoclonal (7B5A1) (Cat. # AAC02)

New Acetyl-Lysine Antibody Mouse Monoclonal (19C4B2.1) (Cat. # AAC03)

New Acetyl-Lysine-HRP Antibody Mouse Monoclonal (19C4B2.1) (Cat. # AAC03-HRP)

New Acetyl-Lysine Affinity Beads (Cat. # AAC04-beads)

Phosphotyrosine Affinity Beads (Cat. # APY03-beads)

Phosphotyrosine-HRP Mouse Monoclonal Antibody 27B10 (Cat. # APY03-HRP)

SUMOylation 2/3 Affinity Beads (Cat. # ASM24-beads)

Ubiquitin Antibody Mouse Monoclonal (Cat. # AUB01)

IgG Control Beads (Cat. # CIG01-beads)

Acetyl-Lysine Control Beads (Cat. # CIG02-beads)

Ubiquitination Control Beads (Cat. # CUB02-beads)

 References  

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    2. Owerbach D. et al. 2005. A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. Biochem. Biophys. Res. Comm. 337, 517-520.
    3. Yang W. and Paschen W. 2015. SUMO proteomics to decipher the SUMO-modified proteome regulated by various diseases. Proteomics. 15, 1181-1191.
    4. Kira B. et al. 2012. SUMOylation in carcinogenesis. Cancer Lett. 316, 113-125.
    5. Eifler K. and Vertegaal A. 2015. SUMOylation-mediated regulation of cell cycle progression and cancer. Trends Biochem. Sci. 40, 779-793.
    6. Amente A. et al. 2012. SUMO-activating SAE1 transcription is positively regulated by Myc. Am. J. Cancer Res. 2, 330-334.
    7. Kessier J. et al. 2012. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 335, 348-353.
    8. Mattoscio D. et al. 2017. Autography regulates UBC9 levels during viral-mediated tumorigenesis. PLoS Pathog. 13, e1006262.
    9. Moschos S. et al. 2010. Expression analysis of Ubc9, the single small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, in normal and malignant tissues. Hum. Pathol. 41, 1286-1298.
    10. Yang W. 2013. Small ubiquitin-like modifier 1-3 conjugation is activated in human astrocytic brain tumors and is required for glioblastoma cell survival. Cancer Sci. 104, 70-77.
    11. Rabellino A. et al. 2017. The role of PIAS SUMO E3- ligases in cancer. Cancer Res. 77, 1-6.
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    16. Cheng J. et al. 2006. Role of deSUMOylation in the development of prostate cancer. Neoplasia. 8, 667-676.
    17. Shen H. et al. 2012. SENP2 regulates hepatocellular carcinoma cell growth by modulating the stability of b-catenin. Asian Pac. J. Cancer Prev. 13, 3583-3587.
    18. Cheng J. 2017. Upregulation of SENP3/SMT3Ip1 promotes epithelial ovarian cancer progression and forecasts poor prognosis. Tumor Biol. 39, 1010428317694543.
    19. Ding X. et al. 2008. Overexpression of SENP3in oral aquamous cell carcinoma and its association with differentiation. Oncol. Rep. 20, 1041-1045.
    20. Wang K. et al. 2014. Inhibition of SENP5 suppresses cell growth and promotes apoptosis in osteosarcoma cells. Exp. Ther. Med. 7, 1691-1695.
    21. Jin Z. et al. 2016. The SMO-specific protease SENP5 controls DNA damage response and promotes tumorigenesis in hepatocellular carcinoma. Eur. Rev. Med. Pharmacol. Sci. 20, 3566-3573.
    22. Qian J. et al. 2013. Inhibition of SEMP6-induced radiosensitization of human hepatocellular carcinoma cells by clocking radiation-induced NF-kappaB activation. Cancer Biother. Radiopharm. 28, 196-200.
    23. Bawa T. et al. 2012. Differential expression of SUMO-specific protease 7 variants regulates epithelial-mesenchymal transition. Proc. Natl. Acad. Sci. USA. 109, 17466-17471.
    24. Etuale. M. et al. 2013. A Novel inhibitor of SUMOylation pathway: Understanding the mechanism of action. UCR. Undergraduate Res. J. 7, 60-65.
    25. Licciardello M. 2014. NITCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation . Oncogene. DOI:10.1038/onc.2014.319.
    26. Bossis G. et al. 2014. The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs. Cell Rep. 7, 1815-1823.
    27. Lalleman-Breitenbach V. et al. 2008. Arsenic degrades PML-PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat. Cell Biol. 10, 547-555.