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The tumor suppressor p53 is rarely (2%) mutated in NB but its functions are diminished in the majority of these tumors. Multiple mechanisms have been identified that attenuate the activity of p53 in MYCN-amplified (MYCN-amp) NB cells, but fewer mechanisms of p53 inactivation have been revealed in MYCN-WT NBs. Thus, a major challenge is to identify novel targeted therapies for high-risk NB (HR-NB) patients, specifically for the large fraction (70%) that present with MYCN-WT. Previously, we identified SETD8, the H4\n                      <jats:sup>K20me1<\/jats:sup>\n                      methyltransferase, as a crucial epigenetic regulator of growth and differentiation in NB. In addition to targeting other non-histone proteins, SETD8 monomethylates p53 on lysine 382 (p53\n                      <jats:sup>K382me1<\/jats:sup>\n                      ), attenuating its pro-apoptotic and growth arrest functions. Genetic and pharmacological (UNC0379) inhibition of SETD8 impairs NB growth\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      IC\n                      <jats:sub>50<\/jats:sub>\n                      and IVTI (\n                      <jats:italic>in vitro<\/jats:italic>\n                      therapeutic index) of SGSS05-NS3, a SETD8 inhibitor, were measured in a broad collection of MYCN-WT and MYCN-amp NB cell lines. We took advantage of RNA-seq transcriptome analysis,\n                      <jats:italic>in vitro<\/jats:italic>\n                      functional assays and\n                      <jats:italic>in vivo<\/jats:italic>\n                      preclinical NB models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      To identify targeted therapies that are less toxic for HR-NB, we evaluated a more specific SETD8 inhibitor with enhanced activity and selectivity, SGSS05-NS3. Our results indicated that in NB cells\n                      <jats:italic>in vitro<\/jats:italic>\n                      treatment with SGSS05-NS3 rescues the canonical p53 functions leading to increases in p53 protein levels and of its target p21 by decreasing p53\n                      <jats:sup>K382me1<\/jats:sup>\n                      , impairing NB cell viability and inducing caspase-dependent cell death. Gene expression profile (RNA-seq analysis) confirmed that the most significantly upregulated genes upon SGSS05-NS3 treatment were among the p53 pathway targets. Pharmacological and genetic SETD8 inhibition restores p53-mediated DNA damage response. In pre-clinical xenograft NB models, pharmacological SETD8 inhibition by SGSS05-NS3 conferred a significant survival advantage in MYCN-WT NB.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study provides further evidence for targeting SETD8 as a therapeutic strategy in NB, alone or in combination with Topotecan.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03565-7","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T11:15:00Z","timestamp":1766142900000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SGSS05-NS3, a covalent SETD8 inhibitor that activates p53 pathway in neuroblastoma"],"prefix":"10.1186","volume":"45","author":[{"given":"Zhihui","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukriti","family":"Bagchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil","family":"Blum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minkui","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Di Bella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Verona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Appella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Giannini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol J.","family":"Thiele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Veschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"3565_CR1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/978-3-031-51292-6_5","volume-title":"Neuroblastoma: Discoveries and Challenges","author":"V Veschi","year":"2024","unstructured":"Veschi V, Durinck K, Thiele CJ, Speleman F. 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The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc. and Cullinan Oncology, Inc. The other authors declare no competing interests.The other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5"}}