Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma
Abstract Cancer cells exploit epigenetic modifications and post-transcriptional regulations to form oncogenic gene expression networks. However, how these machineries collaboratively orchestrate malignancy remains elusive. One of aberrant epigenetic pathways in cancer is Polycomb repressive complex...
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Nature Publishing Group
2025-06-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-025-00561-6 |
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| author | Shunpei Satoh Mariko Hasegawa Ryu Okada Masayuki Haruta Hisanori Takenobu Miki Ohira Takehiko Kamijo |
| author_facet | Shunpei Satoh Mariko Hasegawa Ryu Okada Masayuki Haruta Hisanori Takenobu Miki Ohira Takehiko Kamijo |
| author_sort | Shunpei Satoh |
| collection | DOAJ |
| description | Abstract Cancer cells exploit epigenetic modifications and post-transcriptional regulations to form oncogenic gene expression networks. However, how these machineries collaboratively orchestrate malignancy remains elusive. One of aberrant epigenetic pathways in cancer is Polycomb repressive complex 1 (PRC)-mediated H2AK119 monoubiquitination (H2AK119ub1) with subsequent silencing of tumor suppressor genes. Despite previous efforts, the biological and clinical significance of PRC1 remains unclear in neuroblastoma (NB), an aggressive sympathoadrenal solid tumor in children. In this study, we demonstrated that knockdown of RING1A, one of the E3 ubiquitin ligases of PRC1, reduced cell viability and enrichment of H2AK119ub1 in NB cells. Transcriptional profiling revealed RING1A-specific targets, whose lower expression was associated with poor outcomes in NB patients. Among these genes, BTG2, a component of the CCR4-NOT polyA deadenylase complex, harbored a hypomethylated CpG island occupied by H2AK119ub1 and accessory proteins of noncanonical PRC1.1 (ncPRC1.1). Biological experiments uncovered that BTG2 suppressed NB cell growth in vitro and inhibited tumor formation in vivo. Moreover, BTG2 perturbed cell cycle progression and selectively destabilized the mRNAs of the cyclin genes CCNA2, CCNB1, and CCNB2. In NB patient cohorts, lower expression of BTG2 was associated with poor outcomes and inversely correlated with those cyclin gene expression. Collectively, we have uncovered a crosstalk between epigenetic modifications and post-transcriptional regulations, in which ncPRC1.1-mediated silencing of BTG2 retains cyclin gene expression and cell proliferation in NB. This study provides new insights into how epigenetic pathways contribute to NB malignancy. |
| format | Article |
| id | doaj-art-3f28e84424094d9abd9fc40d2ff4fe3e |
| institution | OA Journals |
| issn | 2157-9024 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj-art-3f28e84424094d9abd9fc40d2ff4fe3e2025-08-20T02:05:42ZengNature Publishing GroupOncogenesis2157-90242025-06-0114111110.1038/s41389-025-00561-6Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastomaShunpei Satoh0Mariko Hasegawa1Ryu Okada2Masayuki Haruta3Hisanori Takenobu4Miki Ohira5Takehiko Kamijo6Research Institute for Clinical Oncology, Saitama Cancer CenterDepartmant of Surgery, Dokkyo Medical University Saitama Medical CenterResearch Institute for Clinical Oncology, Saitama Cancer CenterResearch Institute for Clinical Oncology, Saitama Cancer CenterResearch Institute for Clinical Oncology, Saitama Cancer CenterResearch Institute for Clinical Oncology, Saitama Cancer CenterResearch Institute for Clinical Oncology, Saitama Cancer CenterAbstract Cancer cells exploit epigenetic modifications and post-transcriptional regulations to form oncogenic gene expression networks. However, how these machineries collaboratively orchestrate malignancy remains elusive. One of aberrant epigenetic pathways in cancer is Polycomb repressive complex 1 (PRC)-mediated H2AK119 monoubiquitination (H2AK119ub1) with subsequent silencing of tumor suppressor genes. Despite previous efforts, the biological and clinical significance of PRC1 remains unclear in neuroblastoma (NB), an aggressive sympathoadrenal solid tumor in children. In this study, we demonstrated that knockdown of RING1A, one of the E3 ubiquitin ligases of PRC1, reduced cell viability and enrichment of H2AK119ub1 in NB cells. Transcriptional profiling revealed RING1A-specific targets, whose lower expression was associated with poor outcomes in NB patients. Among these genes, BTG2, a component of the CCR4-NOT polyA deadenylase complex, harbored a hypomethylated CpG island occupied by H2AK119ub1 and accessory proteins of noncanonical PRC1.1 (ncPRC1.1). Biological experiments uncovered that BTG2 suppressed NB cell growth in vitro and inhibited tumor formation in vivo. Moreover, BTG2 perturbed cell cycle progression and selectively destabilized the mRNAs of the cyclin genes CCNA2, CCNB1, and CCNB2. In NB patient cohorts, lower expression of BTG2 was associated with poor outcomes and inversely correlated with those cyclin gene expression. Collectively, we have uncovered a crosstalk between epigenetic modifications and post-transcriptional regulations, in which ncPRC1.1-mediated silencing of BTG2 retains cyclin gene expression and cell proliferation in NB. This study provides new insights into how epigenetic pathways contribute to NB malignancy.https://doi.org/10.1038/s41389-025-00561-6 |
| spellingShingle | Shunpei Satoh Mariko Hasegawa Ryu Okada Masayuki Haruta Hisanori Takenobu Miki Ohira Takehiko Kamijo Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma Oncogenesis |
| title | Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma |
| title_full | Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma |
| title_fullStr | Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma |
| title_full_unstemmed | Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma |
| title_short | Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma |
| title_sort | noncanonical prc1 1 targets btg2 to retain cyclin gene expression and cell growth in neuroblastoma |
| url | https://doi.org/10.1038/s41389-025-00561-6 |
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