title: Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer.
abstract: Exposure to inorganic arsenic in contaminated drinking water poses an environmental public health threat for hundreds of millions of people in the US and around the world. Arsenic is a known carcinogen for skin cancer. However, the mechanism by which arsenic induces skin cancer remains poorly understood. Here, we have shown that arsenic induces p62 expression in an autophagy-independent manner in human HaCaT keratinocytes. In mouse skin, chronic arsenic exposure through drinking water increases p62 protein levels in the epidermis. Nrf2 is required for basal and arsenic-induced p62 up-regulation. p62 knockdown reduces arsenic-induced Nrf2 activity, and induces sustained p21 up-regulation. p62 induction is associated with increased proliferation in mouse epidermis. p62 knockdown had little effect on arsenic-induced apoptosis, while it decreased cell proliferation following arsenic treatment. Our findings indicate that arsenic induces p62 expression to regulate the Nrf2 pathway in human keratinocytes and suggest that targeting p62 may help prevent arsenic-induced skin cancer.
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637, USA. palaks@uchicago.edu.|Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, IL 60637, USA. palaks@uchicago.edu.
authors.forename: Palak
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Biological Sciences and Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA. etrinh3@uic.edu.
authors.forename: Elaine
authors.initials: E
authors.lastname: Trinh
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637, USA. lqiang@cpu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Department of Urology, College of Medicine, and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA. lishixie@uic.edu.
authors.forename: Lishi
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Urology, College of Medicine, and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA. wyhu@uic.edu.
authors.forename: Wen-Yang
authors.initials: WY
authors.lastname: Hu
authors.affiliation: Department of Urology, College of Medicine, and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA. gprins@uic.edu.
authors.forename: Gail S
authors.initials: GS
authors.lastname: Prins
authors.affiliation: Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang 110122, China. jbpi@cmu.edu.cn.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637, USA. yyhe@medicine.bsd.uchicago.edu.|Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, IL 60637, USA. yyhe@medicine.bsd.uchicago.edu.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: He
mesh_terms: D000818:Animals; D001151:Arsenic / Q000009:adverse effects / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D001151:Arsenic
keywords: Nrf2; apoptosis; arsenic; keratinocytes; p62; proliferation