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With neuroendocrine prostate cancer (NEPC) rising due to androgen receptor inhibitor use and lacking effective therapies, the study tests LSD1’s role in NEPC. LSD1 is highly upregulated in NEPC, and LSD1 knockdown or allosteric inhibition reduces NEPC survival and tumor growth in vivo. Mechanistically, LSD1 represses luminal differentiation pathways and reactivates TP53 signaling by promoting TP53 loss at target genes through disrupting LSD1–HDAC interactions and increasing histone acetylation.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lsd1-promotes-prostate-cancer-reprogramming-by-repressing-tp53-signaling-independently-of-its-demethylase-function/383959/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/lsd1-promotes-prostate-cancer-reprogramming-by-repressing-tp53-signaling-independently-of-its-demethylase-function/383959.png","ImageObject",300,407,{"name":92,"@type":93},"นรินทร์","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does LSD1 play in prostate cancer reprogramming and NEPC?","Question",{"text":112,"@type":113},"LSD1 promotes a reprogramming process associated with NEPC and supports NEPC cell survival. The study finds LSD1 is highly upregulated in NEPC compared with adenocarcinoma patient tumors.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does LSD1 inhibition affect NEPC cell survival?",{"text":117,"@type":113},"LSD1 suppression by RNAi or allosteric LSD1 inhibitors reduces NEPC cell survival, while catalytic inhibitors do not show the same effect.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is TP53 signaling central to LSD1’s effect?",{"text":121,"@type":113},"The work shows LSD1 represses TP53-linked pathways and suppresses TP53 activity by reducing TP53 occupancy at target genes. LSD1 inhibition disrupts LSD1–HDAC interactions, increasing histone acetylation at TP53 targets.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},383959,1790560368,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},2336475104957,"https://ap-avatar.wpscdn.com/avatar/22000c4c6bd8a5076e1?x-image-process=image/resize,m_fixed,w_180,h_180&k=1787554080175789136","RESE AR CH  \nARTICLE  \nConflict of interest: JJA reports consulting and speaker’s fees from Astellas Pharma, consulting fees from Dendreon, consulting fees from Merck, consulting fees from Bristol Myers Squibb, and research support to his institution from Astellas Pharma, Zenith Epigenetics, and Beactica. AR reports serving as a member for Voxel Analytics LLC. PSN reports consulting fees from Merck and Bristol Myers Squibb and research support from Janssen for work unrelated to the present studies.  \nCopyright: © 2023, Kumaraswamyet al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nSubmitted: November 23, 2022  \nAccepted: June 28, 2023  \nPublished: August 8, 2023  \nReference information: JCI Insight. 2023;8(15):e167440 .  \n[https://doi.org/10.1172/jci](https://doi.org/10.1172/jci). insight.167440 .  \nLSD1 promotes prostate cancer reprogramming by repressing TP53 signaling independently of its demethylase function  \nAnbarasu Kumaraswamy,1,2 Zhi Duan,1,2 Diana Flores,1,2 Chao Zhang,1,2 Archana Sehrawat,3 Ya-Mei Hu,3,4 Olivia A. Swaim,1,2,5 Eva Rodansky,1,2 William K. Storck,1,2 Joshua A. Kuleape,1,2 Karan Bedi,2,6 Rahul Mannan,7 Xiao-Ming Wang,7,8 Aaron Udager,7 Visweswaran Ravikumar,9 Armand Bankhead III,9 Ilsa Coleman,10 John K. Lee,10 Colm Morrissey,11 Peter S. Nelson,10  \nArul M. Chinnaiyan,2,7,8,12,13 Arvind Rao,2,9,14,15 Zheng Xia,3,4 Joel A. Yates,1,2 and Joshi J. Alumkal1,2,8 1Department of Internal Medicine and 2Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA. 3Knight Cancer Institute and 4Biomedical Engineering Department, Oregon Health & Science University (OHSU), Portland, Oregon, USA. 5College of Literature, Science, and the Arts, and 6Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA. 7Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA. 8Michigan Center for Translational Pathology, Ann Arbor, Michigan, USA. 9Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. 10Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 11Department of Urology, University of Washington, Seattle, Washington, USA. 12Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, USA. 13Howard Hughes Medical Institute, Ann Arbor, Michigan, USA. 14Department of Radiation Oncology and 15Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.  \nLysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cell survival in cancers such as prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since the widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC versus adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors — but not catalytic inhibitors — reduced NEPC cell survival. RNA-Seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1’s catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest t","cbCaiq2Yuy4BpowO","https://ap.wps.com/l/cbCaiq2Yuy4BpowO","pdf",2113201,15,"English","# Conflict of interest and publication details\n## Study aims and background\n## NEPC context and unmet therapeutic needs\n## LSD1 expression and functional testing in NEPC\n## Mechanistic link to TP53 signaling\n## In vivo tumor growth effects and therapeutic implications","[{\"question\":\"What role does LSD1 play in prostate cancer reprogramming and NEPC?\",\"answer\":\"LSD1 promotes a reprogramming process associated with NEPC and supports NEPC cell survival. The study finds LSD1 is highly upregulated in NEPC compared with adenocarcinoma patient tumors.\"},{\"question\":\"How does LSD1 inhibition affect NEPC cell survival?\",\"answer\":\"LSD1 suppression by RNAi or allosteric LSD1 inhibitors reduces NEPC cell survival, while catalytic inhibitors do not show the same effect.\"},{\"question\":\"Why is TP53 signaling central to LSD1’s effect?\",\"answer\":\"The work shows LSD1 represses TP53-linked pathways and suppresses TP53 activity by reducing TP53 occupancy at target genes. LSD1 inhibition disrupts LSD1–HDAC interactions, increasing histone acetylation at TP53 targets.\"}]","LSD1 promotes prostate cancer reprogramming by repressing TP53 signaling independently of its demethylase function | PDF",1790260465,38]