{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:54Z","timestamp":1789448574125,"version":"build-2803163510"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    Diffuse intrinsic pontine glioma (DIPG) is a brain malignancy in children with a dismal prognosis. The high mobility group box 2 (HMGB2) is a member of the HMGB family of chromatin-associated proteins, and is identified as a potential oncogene in various cancers. However, the effects of HMGB2 in DIPG remains unclear. In this study, we observed aberrant expression of HMGB2 in multiple cancer types, with its expression level being negatively correlated with clinical outcomes across pan-cancers. High expression of HMGB2 was determined in DIPG cells, but not in primary brainstem neural progenitor cells (PPCs). Knockdown of HMGB2 significantly inhibited the DIPG cell proliferation and induced cell apoptosis. Intriguingly, bulk RNA sequencing revealed that inhibition of HMGB2 upregulated p53 protein expression and enhanced the activity of p53-p21 axis. Combining HMGB2 inhibitor with a p53-MDM2 inhibitor RG7388 resulted in a synergistic suppression of DIPG cell growth and promoted cell apoptosis by activating the tumor suppressor p53 and p21 expressions\n                    <jats:italic>in vitro<\/jats:italic>\n                    . The animal studies demonstrated that the combination treatment significantly inhibited tumor growth and prolonged the survival of mice bearing orthotopic DIPG tumors. These findings demonstrate that HMGB2 acts as an oncogene in DIPG tumorigenesis, and targeting HMGB2 combined with MDM2 inhibitor provides a novel preclinical basis for the development of DIPG therapeutic strategies.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1867524","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:26:38Z","timestamp":1789446398000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic antitumor effect of HMGB2 targeting combined with MDM2 inhibitor in diffuse intrinsic pontine glioma therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Bochao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyang","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiying","family":"Mai","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaa295","article-title":"Epidemiology of brainstem high-grade gliomas in children and adolescents in the United States, 2000-2017","volume":"23","author":"Patil","year":"2021","journal-title":"Neuro Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1007\/s10143-024-02435-8","article-title":"The relationship between imaging features, therapeutic response, and overall survival in pediatric diffuse intrinsic pontine glioma","volume":"47","author":"Yu","year":"2024","journal-title":"Neurosurg Rev"},{"key":"B3","first-page":"1","article-title":"Declines in cancer death rates among youth: United States, 2001-2021","author":"Curtin","year":"2023","journal-title":"NCHS Data Brief"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16101814","article-title":"Pediatric diffuse midline glioma H3K27-altered: From developmental origins to therapeutic challenges","volume":"16","author":"Mandorino","year":"2024","journal-title":"Cancers (Basel)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2025.0012","article-title":"Pediatric central nervous system cancers, version 2.2023, NCCN clinical practice guidelines in oncology","volume":"20","author":"Gajjar","year":"2022","journal-title":"J Natl Compr Canc Netw"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nox021","article-title":"Diffuse intrinsic pontine gliomas-current management and new biologic insights. Is there a glimmer of hope","volume":"19","author":"Cohen","year":"2017","journal-title":"Neuro Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00239","article-title":"Beyond the blood:brain barrier: The importance of central nervous system (CNS) pharmacokinetics for the treatment of CNS tumors, including diffuse intrinsic pontine glioma","volume":"8","author":"Warren","year":"2018","journal-title":"Front Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41698-017-0033-y","article-title":"Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as an early event","volume":"1","author":"Koschmann","year":"2017","journal-title":"NPJ Precis Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO classification of tumors of the central nervous system: a summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216876","article-title":"Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies","volume":"590","author":"Weisbrod","year":"2024","journal-title":"Cancer Lett"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24098334","article-title":"Structure and functions of HMGB2 protein","volume":"24","author":"Starkova","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/hc9.0000000000000299","article-title":"HMGB2 is a potential diagnostic marker and therapeutic target for liver fibrosis and cirrhosis","volume":"7","author":"Huang","year":"2023","journal-title":"Hepatol Commun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2024.101977","article-title":"HMGB2 is a biomarker associated with poor prognosis promoting radioresistance in glioma by targeting base excision repair pathway","volume":"45","author":"Han","year":"2024","journal-title":"Transl Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2018.09.017","article-title":"HMGB2 promotes the Malignancy of human gastric cancer and indicates poor survival outcome","volume":"84","author":"Cui","year":"2019","journal-title":"Hum Pathol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-018-0219-0","article-title":"HMGB2 is associated with Malignancy and regulates Warburg effect by targeting LDHB and FBP1 in breast cancer","volume":"16","author":"Fu","year":"2018","journal-title":"Cell Commun Signal"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-022-00408-8","article-title":"Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5","volume":"3","author":"Sun","year":"2022","journal-title":"Nat Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2021.08.001","article-title":"The genome sequence archive family: Toward explosive data growth and diverse data types","volume":"19","author":"Chen","year":"2021","journal-title":"Genomics Proteomics Bioinf"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1078","article-title":"Database resources of the national genomics data center, China national center for bioinformation in 2024","volume":"52","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1186\/s40478-021-01270-y","article-title":"TP53 wild-type\/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist","volume":"9","author":"Xu","year":"2021","journal-title":"Acta Neuropathol Commun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/srep45907","article-title":"Effect of agomelatine on memory deficits and hippocampal gene expression induced by chronic social defeat stress in mice","volume":"8","author":"Martin","year":"2017","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1097\/jto.0000000000000584","article-title":"Inhibiting MDM2-p53 interaction suppresses tumor growth in patient-derived non-small cell lung cancer xenograft models","volume":"10","author":"Hai","year":"2015","journal-title":"J Thorac Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1669","article-title":"A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation","volume":"10","author":"Lee","year":"2014","journal-title":"Nat Chem Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-007-0221-2","article-title":"Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome","volume":"85","author":"Teodoro","year":"2007","journal-title":"J Mol Med (Berl)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188556","article-title":"Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting","volume":"1876","author":"Hern\u00e1ndez Borrero","year":"2021","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B25","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1186\/s40478-021-01270-y","article-title":"TP53 wild-type\/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist","volume":"9","author":"Xu","year":"2021","journal-title":"Acta Neuropathol Commun"},{"key":"B26","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.tcb.2020.12.011","article-title":"p53 and tumor suppression: It takes a network","volume":"31","author":"Boutelle","year":"2021","journal-title":"Trends Cell Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.764245","article-title":"Roles of HMGBs in prognosis and immunotherapy: A pan-cancer analysis","volume":"12","author":"Lin","year":"2021","journal-title":"Front Genet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34559","article-title":"GSK-J4: An H3K27 histone demethylase inhibitor, as a potential anti-cancer agent","volume":"153","author":"Dalpatraj","year":"2023","journal-title":"Int J Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noad141","article-title":"Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047)","volume":"25","author":"Monje","year":"2023","journal-title":"Neuro Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21020490","article-title":"Combined targeting of mutant p53 and Jumonji family histone demethylase augments therapeutic efficacy of radiation in H3K27M DIPG","volume":"21","author":"Nikolaev","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030313","article-title":"Mesenchymal transition and PDGFRA amplification\/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas","volume":"7","author":"Puget","year":"2012","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s42003-019-0420-8","article-title":"ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma","volume":"2","author":"Carvalho","year":"2019","journal-title":"Commun Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/s41419-020-02800-7","article-title":"Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells","volume":"11","author":"Wiese","year":"2020","journal-title":"Cell Death Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaw0064","article-title":"Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening","volume":"11","author":"Lin","year":"2019","journal-title":"Sci Transl Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1186\/s12890-022-02110-y","article-title":"Identification of HMGB2 associated with proliferation, invasion and prognosis in lung adenocarcinoma via weighted gene co-expression network analysis","volume":"22","author":"Qiu","year":"2022","journal-title":"BMC Pulm Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1415435","article-title":"HMGB2 drives tumor progression and shapes the immunosuppressive microenvironment in hepatocellular carcinoma: insights from multi-omics analysis","volume":"15","author":"Chen","year":"2024","journal-title":"Front Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmw124","article-title":"Expression of HMGB2 indicates worse survival of patients and is required for the maintenance of Warburg effect in pancreatic cancer","volume":"49","author":"Cai","year":"2017","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.26355\/eurrev_202005_21161","article-title":"Knockdown of HMGB2 inhibits proliferation and invasion of renal tumor cells via the p-38MAPK pathway","volume":"24","author":"He","year":"2020","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"B39","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.biocel.2017.08.010","article-title":"Downregulation of miR-130a promotes cell growth and epithelial to mesenchymal transition by activating HMGB2 in glioma","volume":"93","author":"Tang","year":"2017","journal-title":"Int J Biochem Cell Biol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1177\/1758835920970850","article-title":"Biological functions and theranostic potential of HMGB family members in human cancers","volume":"12","author":"Niu","year":"2020","journal-title":"Ther Adv Med Oncol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201400338","article-title":"Silencing of high-mobility group box 2 (HMGB2) modulates cisplatin and 5-fluorouracil sensitivity in head and neck squamous cell carcinoma","volume":"15","author":"Syed","year":"2015","journal-title":"Proteomics"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01087-6","article-title":"Inflachromene attenuates seizure severity in mouse epilepsy models via inhibiting HMGB1 translocation","volume":"44","author":"Dai","year":"2023","journal-title":"Acta Pharmacol Sin"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1867524\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:26:39Z","timestamp":1789446399000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1867524\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":42,"alternative-id":["10.3389\/fonc.2026.1867524"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1867524","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]},"article-number":"1867524"}}