Exogenous N-Acetylgalactosamine-4-sulfatase (Arylsulfatase B) Leads to Melanoma Apoptosis by Constitutive Photomorphogenic 1 (COP1)

Exogenous N-Acetylgalactosamine-4-sulfatase (Arylsulfatase B) Leads to Melanoma Apoptosis by Constitutive Photomorphogenic 1 (COP1) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exogenous N-Acetylgalactosamine-4-sulfatase (Arylsulfatase B) Leads to Melanoma Apoptosis by Constitutive Photomorphogenic 1 (COP1) Joanne K Tobacman, Insug O-Sullivan, Sumit Bhattacharyya, Herbert E. Whiteley, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5538859/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Treatment by exogenous, bioactive, recombinant human N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) markedly reduced the number and volume of pulmonary melanomas in C57BL/6J mice inoculated intravenously with B16F10 melanoma cells. ARSB treatment induced apoptosis of the melanomas and of human A375 melanoma cells by increase in expression of the E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1), an inhibitor of ultraviolet B-stimulated signaling 5 – 12 . The corresponding inhibitory effects of COP1 on UVB-stimulated plant growth and on melanoma, a malignancy stimulated by UVB exposure, provide new insight into melanoma pathogenesis. Here, we show that in melanoma tissues and human melanoma cells, COP1 suppressed nuclear ETS-1 and the ETS-1-mediated expression of BCL2, leading to increased cytoplasmic cytochrome c, caspase-3/7 activation, and apoptosis. Exogenous ARSB, acting through insulin-like growth factor 2 receptor (IGF2R), reduced expression of carbohydrate sulfotransferase (CHST)15. Inhibition of CHST15, which adds a 6-sulfate group to C4S and is increased in several malignancies 32 – 38 , blocked activation of the transmembrane receptor ROR (Receptor tyrosine-kinase like Orphan Receptor)1 and of phospho(Ser473)-AKT1, leading to increased nuclear FOXO3 and COP1 expression. This negative regulation of phospho(Ser473)-AKT1 reflects the profound impact of rhARSB and chondroitin sulfation on regulation of critical cell signaling which enables the COP1-mediated apoptotic pathway and inhibition of melanoma growth. Cancer Biology N-acetylgalactosamine-4-sulfatase melanoma COP1 arylsulfatase B chondroitin sulfate CHST15 Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5538859","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":385512041,"identity":"eabafdd1-ffca-443b-9860-90c26787c0e3","order_by":0,"name":"Joanne K Tobacman","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAlklEQVRIiWNgGAWjYBACxh4GxgcMBiBmAtFamJkNSNPCwMPMJgFhEauFuef8sWqeAjsGfvYcAyId1tvMdpvHIJlBsucNsVr6mUFaDjAY3CDaFqCWYpAWe+K1AB3GDLZFgmgtPYeNJecYJPNInHlWQJwWw57Ehx/e/LGT429P3kCklgYIzUOcchCQJ17pKBgFo2AUjFgAAL4yI87teyM0AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7220-3419","institution":"University of Illinois Chicago and Jesse Brown VAMC","correspondingAuthor":true,"prefix":"","firstName":"Joanne","middleName":"K","lastName":"Tobacman","suffix":""},{"id":385512042,"identity":"354bb098-6043-4cf0-82d4-5cc12ca11b9e","order_by":1,"name":"Insug O-Sullivan","email":"","orcid":"","institution":"University of Illinois Chicago and Jesse Brown VAMC","correspondingAuthor":false,"prefix":"","firstName":"Insug","middleName":"","lastName":"O-Sullivan","suffix":""},{"id":385512043,"identity":"5ebf8e88-782e-4e35-854c-6a75802a48d8","order_by":2,"name":"Sumit Bhattacharyya","email":"","orcid":"","institution":"Jesse Brown VAMC","correspondingAuthor":false,"prefix":"","firstName":"Sumit","middleName":"","lastName":"Bhattacharyya","suffix":""},{"id":385512044,"identity":"6a951be9-c5e8-43f6-891a-d00fef955059","order_by":3,"name":"Herbert E. 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ARSB treatment induced apoptosis of the melanomas and of human A375 melanoma cells by increase in expression of the E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1), an inhibitor of ultraviolet B-stimulated signaling \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10 CR11\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The corresponding inhibitory effects of COP1 on UVB-stimulated plant growth and on melanoma, a malignancy stimulated by UVB exposure, provide new insight into melanoma pathogenesis. Here, we show that in melanoma tissues and human melanoma cells, COP1 suppressed nuclear ETS-1 and the ETS-1-mediated expression of BCL2, leading to increased cytoplasmic cytochrome c, caspase-3/7 activation, and apoptosis. Exogenous ARSB, acting through insulin-like growth factor 2 receptor (IGF2R), reduced expression of carbohydrate sulfotransferase (CHST)15. Inhibition of CHST15, which adds a 6-sulfate group to C4S and is increased in several malignancies \u003csup\u003e\u003cspan additionalcitationids=\"CR33 CR34 CR35 CR36 CR37\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, blocked activation of the transmembrane receptor ROR (Receptor tyrosine-kinase like Orphan Receptor)1 and of phospho(Ser473)-AKT1, leading to increased nuclear FOXO3 and COP1 expression. This negative regulation of phospho(Ser473)-AKT1 reflects the profound impact of rhARSB and chondroitin sulfation on regulation of critical cell signaling which enables the COP1-mediated apoptotic pathway and inhibition of melanoma growth.\u003c/p\u003e","manuscriptTitle":"Exogenous N-Acetylgalactosamine-4-sulfatase (Arylsulfatase B) Leads to Melanoma Apoptosis by Constitutive Photomorphogenic 1 (COP1)","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-02-06 13:16:56","doi":"10.21203/rs.3.rs-5538859/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2024-12-03 06:50:48","doi":"10.21203/rs.3.rs-5538859/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"625eb60e-a707-4f82-9e0e-d672fa4213c7","owner":[],"postedDate":"February 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":43682469,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2024-12-03T06:50:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-06 13:16:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-5538859","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5538859","identity":"rs-5538859","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}