Yu-Ying He

Associate Professor
Websites
Research Summary
Our research addresses the fundamental question of how cells respond to radiation and chemicals from internal or external sources to cause cancer, with a focus on skin cancer. We use in vitro systems, clinically relevant animal models, genetically modified mouse models, and human patient samples to elucidate how intrinsic and extrinsic factors regulate DNA repair, DNA damage response, and cellular homeostasis in order to understand cancer susceptibility. Because skin is an epithelial tissue, our findings are relevant to cancers of other epithelial tissues, and our research has the potential to identify new targets and strategies to improve prevention and treatment for both skin and other epithelial cancers. Our long-term goal is to identify previously unrecognized, therapeutically accessible molecular regulatory networks that predict susceptibility to skin cancer, and to improve our ability to prevent and treat it. (i) Role of autophagy and p62 in tumor initiation and progression. Macroautophagy (hereafter autophagy) is a catabolic process by which cellular proteins, cytoplasm, and organelles are captured and targeted for proteolytic degradation in lysosomes. Autophagy dysfunction is associated with multiple human diseases, such as neurodegeneration, microbial infection, metabolic diseases, cardiovascular diseases, aging, and cancer. The multidomain protein p62/A170/SQSTM1 (hereafter p62) has been shown to be both a selective autophagy substrate and an autophagy adaptor protein that acts as a link between ubiquitination and autophagy. Autophagy is a pleiotropic cell survival mechanism with both pro- and anti-tumor effects. We focus on elucidating the regulatory and functional role of autophagy in skin carcinogenesis and cancer progression. (ii) Molecular control of DNA damage response. Two crucial DNA damage response processes in tumor suppression are apoptosis and senescence, i.e. when the DNA damage burden is large, cells "commit suicide", or terminally differentiate. Dysregulation of apoptosis or senescence promotes tumor initiation and progression. Our research is centered on understanding the molecular basis for controlling DNA damage response. (iii) Molecular control of DNA repair. We focus on investigation of the molecular mechanisms controlling the versatile DNA repair pathway nucleotide excision repair (NER). NER eliminates a wide variety of helix-distorting base lesions induced by ultraviolet B (UVB) radiation, tobacco smoking, cisplatin and oxidative damage. Since key NER proteins are difficult to target directly, identification of upstream regulators has the potential to provide valuable targets for enhancing NER and therefore tumor suppression. However, the molecular signaling pathways regulating NER has been poorly understood. We focus on the molecular mechanisms in regulating NER capacity. These findings have the potential to yield safe and efficient targets to improve DNA repair capacity and thereby to prevent skin cancer and other epithelial cancers. (iv) Extrinsic control of DNA repair and DNA damage response. The mechanisms by which extrinsic factors cause skin cancer can define molecular targets for better prevention and therapy. Organ transplant recipients (OTRs) have a 65 to 250-fold increased risk of developing skin squamous cell carcinoma caused by treatment with immunosuppressants, and immunosuppression has been widely assumed to be the major extrinsic cause for increased skin cancer susceptibility. However, the molecular mechanism by which this occurs was unknown. We focus on the cell-autonomous molecular mechanism of skin tumorigenesis caused by immunosuppressive drugs. These findings have the potential to provide new opportunities and targets for developing better strategies to reduce the burden of this devastating disease in OTRs, without compromising the life-saving attributes of immunosuppressive drugs.
Keywords
Skin Cancer, Melanoma, Autophagy, Epigenetics, DNA damage, Ultraviolet radiation, Photobiology
Education
  • Chinese Academy of Sciences, China, PhD Organic Chemistry 07/2000
Biosciences Graduate Program Association
Publications
  1. Sample A, Zhao B, Qiang L, He YY. Adaptor protein p62 promotes skin tumor growth and metastasis and is induced by UVA radiation. J Biol Chem. 2017 09 08; 292(36):14786-14795. View in: PubMed

  2. Yang S, Qiang L, Sample A, Shah P, He YY. NF-?B Signaling Activation Induced by Chloroquine Requires Autophagosome, p62 Protein, and c-Jun N-terminal Kinase (JNK) Signaling and Promotes Tumor Cell Resistance. J Biol Chem. 2017 02 24; 292(8):3379-3388. View in: PubMed

  3. Sample A, He YY. Autophagy in UV Damage Response. Photochem Photobiol. 2017 07; 93(4):943-955. View in: PubMed

  4. Zhang T, Sheng Z, Du W. Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling. Mech Dev. 2016 08; 141:4-13. View in: PubMed

  5. Sheng Z, Yu L, Zhang T, Pei X, Li X, Zhang Z, Du W. ESCRT-0 complex modulates Rbf-mutant cell survival by regulating Rhomboid endosomal trafficking and EGFR signaling. J Cell Sci. 2016 05 15; 129(10):2075-84. View in: PubMed

  6. Qiang L, Zhao B, Shah P, Sample A, Yang S, He YY. Autophagy positively regulates DNA damage recognition by nucleotide excision repair. Autophagy. 2016; 12(2):357-68. View in: PubMed

  7. Chastkofsky MI, Bie W, Ball-Kell SM, He YY, Tyner AL. Protein Tyrosine Kinase 6 Regulates UVB-Induced Signaling and Tumorigenesis in Mouse Skin. J Invest Dermatol. 2015 Oct; 135(10):2492-2501. View in: PubMed

  8. Liu H, Yue J, Lei Q, Gou X, Chen SY, He YY, Wu X. Ultraviolet B Inhibits Skin Wound Healing by Affecting Focal Adhesion Dynamics. Photochem Photobiol. 2015 Jul-Aug; 91(4):909-16. View in: PubMed

  9. Kim Y, He YY. Ultraviolet radiation-induced non-melanoma skin cancer: Regulation of DNA damage repair and inflammation. Genes Dis. 2014 Dec 01; 1(2):188-198. View in: PubMed

  10. Shah P, He YY. Molecular regulation of UV-induced DNA repair. Photochem Photobiol. 2015 Mar-Apr; 91(2):254-64. View in: PubMed

  11. Ming M, Zhao B, Shea CR, Shah P, Qiang L, White SR, Sims DM, He YY. Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge. J Allergy Clin Immunol. 2015 Apr; 135(4):936-45.e4. View in: PubMed

  12. Zhao B, Shah P, Budanov AV, Qiang L, Ming M, Aplin A, Sims DM, He YY. Sestrin2 protein positively regulates AKT enzyme signaling and survival in human squamous cell carcinoma and melanoma cells. J Biol Chem. 2014 Dec 26; 289(52):35806-14. View in: PubMed

  13. Ming M, Han W, Zhao B, Sundaresan NR, Deng CX, Gupta MP, He YY. SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer Res. 2014 Oct 15; 74(20):5925-33. View in: PubMed

  14. Qiang L, He YY. Autophagy deficiency stabilizes TWIST1 to promote epithelial-mesenchymal transition. Autophagy. 2014 Oct 01; 10(10):1864-5. View in: PubMed

  15. Ming M, Zhao B, Qiang L, He YY. Effect of immunosuppressants tacrolimus and mycophenolate mofetil on the keratinocyte UVB response. Photochem Photobiol. 2015 Jan-Feb; 91(1):242-7. View in: PubMed

  16. Qiang L, Zhao B, Ming M, Wang N, He TC, Hwang S, Thorburn A, He YY. Regulation of cell proliferation and migration by p62 through stabilization of Twist1. Proc Natl Acad Sci U S A. 2014 Jun 24; 111(25):9241-6. View in: PubMed

  17. Ming M, Qiang L, Zhao B, He YY. Mammalian SIRT2 inhibits keratin 19 expression and is a tumor suppressor in skin. Exp Dermatol. 2014 Mar; 23(3):207-9. View in: PubMed

  18. Kim I, He YY. Targeting the AMP-Activated Protein Kinase for Cancer Prevention and Therapy. Front Oncol. 2013; 3:175. View in: PubMed

  19. Qiang L, Wu C, Ming M, Viollet B, He YY. Autophagy controls p38 activation to promote cell survival under genotoxic stress. J Biol Chem. 2013 Jan 18; 288(3):1603-11. View in: PubMed

  20. Zhao B, Ming M, He YY. Suppression of PTEN transcription by UVA. J Biochem Mol Toxicol. 2013 Feb; 27(2):184-91. View in: PubMed

  21. Han W, Soltani K, Ming M, He YY. Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis. Cancer Prev Res (Phila). 2012 Sep; 5(9):1155-62. View in: PubMed

  22. Han W, Ming M, Zhao R, Pi J, Wu C, He YY. Nrf1 CNC-bZIP protein promotes cell survival and nucleotide excision repair through maintaining glutathione homeostasis. J Biol Chem. 2012 May 25; 287(22):18788-95. View in: PubMed

  23. Ming M, He YY. PTEN in DNA damage repair. Cancer Lett. 2012 Jun 28; 319(2):125-129. View in: PubMed

  24. Ming M, Feng L, Shea CR, Soltani K, Zhao B, Han W, Smart RC, Trempus CS, He YY. PTEN positively regulates UVB-induced DNA damage repair. Cancer Res. 2011 Aug 01; 71(15):5287-95. View in: PubMed

  25. Han W, Ming M, He YY. Caffeine promotes ultraviolet B-induced apoptosis in human keratinocytes without complete DNA repair. J Biol Chem. 2011 Jul 01; 286(26):22825-32. View in: PubMed

  26. Ming M, Shea CR, Feng L, Soltani K, He YY. UVA induces lesions resembling seborrheic keratoses in mice with keratinocyte-specific PTEN downregulation. J Invest Dermatol. 2011 Jul; 131(7):1583-6. View in: PubMed

  27. Thompson EA, Zhu S, Hall JR, House JS, Ranjan R, Burr JA, He YY, Owens DM, Smart RC. C/EBPa expression is downregulated in human nonmelanoma skin cancers and inactivation of C/EBPa confers susceptibility to UVB-induced skin squamous cell carcinomas. J Invest Dermatol. 2011 Jun; 131(6):1339-46. View in: PubMed

  28. Ming M, Shea CR, Guo X, Li X, Soltani K, Han W, He YY. Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. Proc Natl Acad Sci U S A. 2010 Dec 28; 107(52):22623-8. View in: PubMed

  29. Zhao B, He YY. Recent advances in the prevention and treatment of skin cancer using photodynamic therapy. Expert Rev Anticancer Ther. 2010 Nov; 10(11):1797-809. View in: PubMed

  30. Lei X, Liu B, Han W, Ming M, He YY. UVB-Induced p21 degradation promotes apoptosis of human keratinocytes. Photochem Photobiol Sci. 2010 Dec; 9(12):1640-8. View in: PubMed

  31. Koker EB, Bilski PJ, Motten AG, Zhao B, Chignell CF, He YY. Real-time visualization of photochemically induced fluorescence of 8-halogenated quinolones: lomefloxacin, clinafloxacin and Bay3118 in live human HaCaT keratinocytes. Photochem Photobiol. 2010 Jul-Aug; 86(4):792-7. View in: PubMed

  32. Han W, Ming M, He TC, He YY. Immunosuppressive cyclosporin A activates AKT in keratinocytes through PTEN suppression: implications in skin carcinogenesis. J Biol Chem. 2010 Apr 09; 285(15):11369-77. View in: PubMed

  33. Zhao B, Yin JJ, Bilski PJ, Chignell CF, Roberts JE, He YY. Enhanced photodynamic efficacy towards melanoma cells by encapsulation of Pc4 in silica nanoparticles. Toxicol Appl Pharmacol. 2009 Dec 01; 241(2):163-72. View in: PubMed

  34. Ming M, He YY. PTEN: new insights into its regulation and function in skin cancer. J Invest Dermatol. 2009 Sep; 129(9):2109-12. View in: PubMed

  35. Zhao B, He YY, Chignell CF, Yin JJ, Andley U, Roberts JE. Difference in phototoxicity of cyclodextrin complexed fullerene [(gamma-CyD)2/C60] and its aggregated derivatives toward human lens epithelial cells. Chem Res Toxicol. 2009 Apr; 22(4):660-7. View in: PubMed

  36. Han W, He YY. Requirement for metalloproteinase-dependent ERK and AKT activation in UVB-induced G1-S cell cycle progression of human keratinocytes. Photochem Photobiol. 2009 Jul-Aug; 85(4):997-1003. View in: PubMed