| Literature DB >> 35857643 |
Shivendra Singh1, Ahmed Abu-Zaid1, Hongjian Jin2, Jie Fang1, Qiong Wu1, Tingting Wang3, Helin Feng4, Waise Quarni1, Ying Shao5, Lily Maxham5, Alireza Abdolvahabi6, Mi-Kyung Yun7, Sivaraja Vaithiyalingam7,8, Haiyan Tan7,9, John Bowling6, Victoria Honnell10, Brandon Young6, Yian Guo11, Richa Bajpai12, Shondra M Pruett-Miller12, Gerard C Grosveld13, Mark Hatley14, Beisi Xu2, Yiping Fan2, Gang Wu2, Eleanor Y Chen15, Taosheng Chen6, Peter W Lewis16, Zoran Rankovic6, Yimei Li11, Andrew J Murphy1, John Easton5, Junmin Peng7,9, Xiang Chen5, Ruoning Wang3, Stephen W White7,10, Andrew M Davidoff1, Jun Yang1,10,17.
Abstract
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1+ RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.Entities:
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Year: 2022 PMID： 35857643 PMCID： PMC9548378 DOI： 10.1126/scitranslmed.abq2096
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 19.319