Radiation and Cancer Biology
Yi Sun, MD, PhD: Director of Radiation & Cancer Biology
The Sun laboratory is focused on understanding the molecular mechanisms involved in regulation of apoptosis, angiogenesis, and radioresistance by SCF E3 ubiquitin ligases and p53 signal pathways with the ultimate aim of identifying and validating targets for mechanism-driven, anti-cancer drug discovery.
1. SAG-SCF E3 ubiquitin ligases in regulation of apoptosis, carcinogenesis and angiogenesis
SAG (Sensitive to Apoptosis Gene, also known as RBX2 or ROC2) was cloned in Sun laboratory. SAG forms active E3 ubiquitin ligases of SCF (Skp1, cullin1 and F-box protein) and VCB (VHL-Elongin-C/B) to promote the ubiquitination and degradation of a number of cellular critical proteins, such as p27, caspase-3, HIF-1α, c-Jun, and IkBα, thus regulating proliferation, apoptosis, hypoxia response, and carcinogenesis. SAG is over-expressed in non-small lung cell carcinoma, which correlates with poor prognosis. Physiological functions of SAG are being studied using constitutive knockout and conditional knockout.
2. RPS27L (Ribosomal Protein S27-Like) as a novel p53 target that regulates p53-induced apoptosis
RPS27L, a novel ribosomal like gene, initially identified in Sun laboratory as a p53-inducible gene from an genome profiling experiment. Further characterization of RPS27L revealed that it is a novel p53 target that mediates p53-induced apoptosis through inhibiting Mdm2. Physiological functions of RPS27L are being studied using constitutive knockout and conditional knockout.
3. Identification and validation of novel radiosensitizing targets
We have conducted a siRNA library screening for potential targets whose silencing induces radiosensitization. Among 8,800 “druggable” target genes screened, we identified and confirmed 23 potential candidates and one third of these candidate hits centered in one particular ubiquitin pathway. We are currently conducting the follow-up experiments to elucidate the mechanism of action.
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Recent Publications directly from the Sun Lab (from a total of 183)
- He, H., and Sun, Y.: Ribosomal protein S27L is a direct p53 target that regulates apoptosis. Oncogene, 26: 2707-2716, 2007.
- Gu, Q, Tan, M., and Sun, Y.: SAG/ROC2/Rbx2 is a novel AP-1 target that promotes c-Jun degradation and inhibits TPA induced neoplastic transformation. Cancer Res. 67: 3616-3625, 2007.
- Gu, Q., Bowden, G.T., Normolle, D., Sun, Y.: SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and IkB-α/NF-kB. J. Cell Biol. 178:1009-1023, 2007. PMCID2064624.
- Tan, M., Gu, Q., He, H., Pamarthy, D., Gemenza, G.L., and Sun, Y.: SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1α ubiquitination and degradation. Oncogene, 27: 1404-1411, 2008.
- Zheng, M., Morgan-Lappe, S., Yang, J., Bockbrader, K. M., Pamarthy, D., Thomas, D., Fesik, S., and Sun, Y.: Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by siRNA silencing of tumor necrosis factor receptor-associated factor-2. Cancer Res. 68:7570-7578, 2008. PMCID2597026.
- Tan, M., Davis, S., Saunders, T., Zhu Y., and Sun, Y.: RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued via simultaneously loss of p27. Proc. Natl. Acad. Sci., USA. 106: 6203-6208, 2009 Mar 26. PMID: 19325126.
- Jia, L. J., Soengas, M. and Sun, Y.: ROC1/RBX1 E3 ubiquitin ligase knockdown suppresses tumor cell growth via sequential induction of G2/M arrest, apoptosis and senescence. Cancer Res. 69:4974-82, 2009. NIHMS123568.
- Wang, Z.*, Zheng, M.*, Li, Z., Li, R., Jia, L., Xiong, X., Southall, N., Wang, S., Xia, M., Austin, C.P., Zheng, W., Xie, Z. and Sun, Y.: Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition. Cancer Res. 69: 6556-6564, 2009. NIHMS127313.
- Jia, L., Yang, J., Hao, X., Xiong, X., Zheng, M., He, H., Xu, L., and Sun, Y.: Validation of SAG/RBX2/ ROC2 E3 ubiquitin ligase as an anti-cancer and radio-sensitizing target. Clinic Cancer Res. 16:814-824, 2010.
- Xiong, X., Zhao, Y., He, H., and Sun, Y.: Ribosomal protein S27-like or S27 interplays with p53-Mdm2 axis as a target, substrate and a regulator. Oncogene, 30: 1798-1811, 2011. Advance online publication, 20 December 2010; doi:10.1038/onc.2010.569.
- Jia, L., Bickel, J., Wu, J., Morgan, M. A., Li, H., Yu, X., Chan, R C., and Sun, Y.: RBX1 (RING-box protein 1) E3 ubiquitin ligase is required for genomic integrity by modulating DNA replication licensing proteins. J. Biol Chem. JBC 286: 3379-3386, 2011. Published online on Nov. 29, 2010 as MS. M110.188425. http://www.jbc.org/cgi/doi/10.1074/jbc.M110.188425.
- Jia, L., Li, H., and Sun, Y.: Induction of p21-dependent senescence by a NAE inhibitor, MLN4924 as a mechanism of growth suppression. Neoplasia 13:561-569, 2011.
- Tan, M*., Li, Y*., Yang, R., Xi., N., and Sun, Y.: Inactivation of SAG E3 ubiquitin ligase blocks embryonic stem cell differentiation and sensitizes leukemia cells to retinoid acid. PLoS One, 6(11):e27726. PLoS One. 6(11):e27726. Epub 2011 Nov 15.
- Zhao, Y., Xiong, X., and Sun, Y.: DEPTOR, an mTOR inhibitor, is a physiological substrate of SCFβTrCP E3 ubiquitin ligase and regulates survival and autophagy. Mol Cell, 44:304-316, 2011.
- Tan, M*., Zhao, Y*., Kim, S., Liu, M., Jia, L., Saunders, T., Zhu, Y., and Sun, Y.: SAG/RBX2-CUL1/5-FBXW7 E3 ubiquitin ligase regulates vasculogenesis and differentiation by targeting NF1 for degradation. Dev. Cell, 21: 1062-1076, 2011.
- Wei, D., Li, H., Yu, J., Sebolt, J. T., Zhao, L., Lawrence, T. S., Smith, P. G., Morgan, M. A., and Sun, Y.: Radiosensitization of human pancreatic cancer cells by MLN4924, an investigational NEDD8-activating enzyme inhibitor. Cancer Res., 72: 282-293, 2012.
- Zhao, Y., and Sun, Y.: Cullin-RING ligases as attractive anti-cancer targets. Curr Pharm Des. 19: 3215-3225, 2013.
- Zhou, W., Wei, W. and Sun, Y.: Genetically engineered mouse models for functional studies of SCF E3 ubiquitin ligases. Cell Res. 23: 599-619, 2013.
- Tan, M.*, Li, H.*, and Sun, Y.: Endothelial deletion of Sag/Rbx2/Roc2 E3 ligase causes embryonic lethality and blocks tumor angiogenesis. Oncogene, 33:5211-20, 2014, 2013 Nov 11. doi: 10.1038/onc.2013.473. [Epub ahead of print] PMID:2421357
- Li, H.*, Tan, M.*, Jia, L., Wei, D., Zhao, Y., Chen, G., Xu, J., Zhao, L., Thomas, D., Beer, D., and Sun, Y.: Inactivation of Sag/Rbx2/Roc2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis. J. Clin. Invest., 124:835-846, 2014.
- Xiong, X.*, Zhao, Y.*, Tang, F., Thomas, D., Wang, X., Liu, Y., Zheng, P., and Sun, Y.: Ribosomal protein S27-like is a physiological inhibitor of p53 that paradoxically suppresses tumorigenesis. eLife. Aug. 2014, http://dx.doi.org/10.7554/eLife.02236.
- Zhao, Y., Wei, D., Morgan, M.A., and Sun, Y.: Targeting neddylation pathways to inactivate Cullin-RING ligases for anti-cancer therapy. Antioxid Redox Signal., 21: 2383-2400, 2014.
- Zhou, W., Xu, J. Zhao, Y., and Sun, Y.: SAG/RBX2 is a novel substrate of NEDD4-1 E3 ubiquitin ligase and mediates NEDD4-1 induced chemosensitization. Oncotarget, 5:6746-55, 2014.
- Li, H., Sun, G. Y., Zhao, Y., Thomas, D., Greenson, J. K., Zalupski, M. M., Ben-Josef, E., and Sun, Y.: DEPTOR has growth suppression activity against pancreatic cancer cells. Oncotarget, in press.
- Tan, M., Li, H., and Sun, Y.: Inactivation of Sag/Rbx2/Roc2 E3 ubiquitin ligase triggers senescence and inhibits Kras-induced immortalization. Neoplasia, in press.