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The study identifies CDKN1A/p21 as a central hub in polyploid giant cancer cells (PGCC) and early progeny, with p21 localized to the cytoplasm in PGCC. Blocking p21 expression with UC2288 prevents acid ceramidase induction and suppresses PGCC formation and progeny generation, indicating p21 acts upstream of acid ceramidase.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/transcriptome-analysis-of-polyploid-giant-cancer-cells-and-their-progeny-reveals-a-functional-role-for-p21-in-polyploidization-and-depolyploidization/342659/",{"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/transcriptome-analysis-of-polyploid-giant-cancer-cells-and-their-progeny-reveals-a-functional-role-for-p21-in-polyploidization-and-depolyploidization/342659.png","ImageObject",300,407,{"name":92,"@type":93},"Olivia Brown","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-24","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What experimental strategy was used to study polyploidization and depolyploidization?","Question",{"text":112,"@type":113},"The study uses an RNA-seq approach to capture transcriptomic changes as cancer cells progress through polyploidization and depolyploidization under stress.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which gene was identified as the central regulator in PGCC and early progeny?",{"text":117,"@type":113},"CDKN1A/p21 was identified as the major hub associated with PGCC and early progeny, with increased p21 expression in PGCC limited to the cytoplasm.",{"name":119,"@type":110,"acceptedAnswer":120},"How does p21 influence acid ceramidase and PGCC formation?",{"text":121,"@type":113},"Blocking p21 with UC2288 prevents induction of acid ceramidase and inhibits both PGCC formation from parental cells and generation of progeny from PGCC.","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},342659,1790211508,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"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},16904993612988,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","RESEARCH ARTICLE  \nTranscriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization  \nReceived for publication, October 7, 2023, and in revised form, February 3, 2024 Published, Papers in Press, March 4, 2024, [https://doi.org/10.1016/j.jbc.2024.107136](https://doi.org/10.1016/j.jbc.2024.107136)  \nShai White-Gilbertson 1, Ping Lu 1, Ozge Saatci2, Ozgur Sahin2, Joe R. Delaney2, Besim Ogretmen2, and Christina Voelkel-Johnson 1,2, *  \nFrom the 1Department of Microbiology & Immunology, and 2Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA  \nReviewed by members of the JBC Editorial Board. Edited by George M. Carman  \nPolyploid giant cancer cells (PGCC) are frequently detected in tumors and are increasingly recognized for their roles in chromosomal instability and associated genome evolution that leads to cancer recurrence. We previously reported that therapy stress promotes polyploidy, and that acid ceramidase plays a role in depolyploidization. In this study, we used an RNA-seq approach to gain a better understanding of the underlying transcriptomic changes that occur as cancer cells progress through polyploidization and depolyploidization. Our results revealed gene signatures that are associated with disease-free and/or overall survival in several cancers and identified the cell cycle inhibitor CDKN1A/p21 as the major hub in PGCC and early progeny. Increased expression of p21 in PGCC was limited to the cytoplasm. We previously demonstrated that thesphingolipid enzyme acid ceramidase is dispensable for polyploidization upon therapy stress but plays a crucial role indepolyploidization. The current study demonstrates that treatment of cells with ceramide is not sufficient for p53-independent induction of p21 and that knockdown of acid ceramidase, which hydrolyzes ceramide, does not interfere with upregulation of p21. In contrast, blocking the expression of p21 with UC2288 prevented the induction of acid ceramidase and inhibited both the formation of PGCC from parental cells as well as the generation of progeny from PGCC. Taken together, our data suggest that p21 functions upstream of acid ceramidase and plays an important role in polyploidization and depolyploidization.  \nPolyploidy, also known as whole genome duplication, has a protective effect in highly differentiated tissues such as the heart, liver, or muscle but is associated with poor prognosis in cancer due to increased genomic instability (1, 2). Stress within the tumor microenvironment or in response to therapy promotes polyploidy, particularly in cells with dysfunctional cell cycle regulation (3). Polyploid giant cancer cells (PGCC) are present in about one-third of tumors and while they present only a small fraction of the total cells, the danger lies in their  \n* For correspondence: Christina Voelkel-Johnson, [johnsocv@musc.edu](johnsocv@musc.edu).  \nability to undergo depolyploidization with subsequent generation of progeny with self-renewal features (4, 5). The parallels between early embryonic development and PGCC suggest that dedifferentiation and reactivation of embryonic programs could be responsible for the plasticity and pluripotency observed in this subpopulation (5–8). Because PGCC promote tumor heterogeneity, therapy resistance, and tumor recurrence, they have been described as the “evil roots of cancer” orthe “keystone species” within the tumor microenvironment (9–12). Despite detailed morphological description of these cells in human cancer specimen as well as studies in animal models and in cell culture, mechanisms involving polyploidization and depolyploidization in malignancy remain incompletely understood (13–15).  \nThe expression of acid ceramidase, a lysosomal enzyme in the sphingolipid pathway that hydrolyses the pro-apoptoticsphingolipid ceramide to sphingosine, is elevated in several malignancies ","cbCaithJIWk4LS81","https://ap.wps.com/l/cbCaithJIWk4LS81","pdf",3578131,15,"English","# Background and study rationale\n## Polyploidy in cancer and PGCC properties\n## Acid ceramidase and stress-driven depolyploidization\n# Transcriptomic approach and key findings\n## RNA-seq strategy for polyploidization/depolyploidization\n## p21/CDKN1A as a major hub and cytoplasmic localization\n# Functional validation\n## Effects of ceramide and acid ceramidase knockdown\n## Inhibition of p21 and impact on ceramidase and PGCC dynamics","[{\"question\":\"What experimental strategy was used to study polyploidization and depolyploidization?\",\"answer\":\"The study uses an RNA-seq approach to capture transcriptomic changes as cancer cells progress through polyploidization and depolyploidization under stress.\"},{\"question\":\"Which gene was identified as the central regulator in PGCC and early progeny?\",\"answer\":\"CDKN1A/p21 was identified as the major hub associated with PGCC and early progeny, with increased p21 expression in PGCC limited to the cytoplasm.\"},{\"question\":\"How does p21 influence acid ceramidase and PGCC formation?\",\"answer\":\"Blocking p21 with UC2288 prevents induction of acid ceramidase and inhibits both PGCC formation from parental cells and generation of progeny from PGCC.\"}]","Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization | PDF",1790047592,38]