Pub Date : 2024-11-11DOI: 10.1038/s41388-024-03217-8
Constantine S. Mitsiades, Nicholas Mitsiades, Vassiliki Poulaki, Robert Schlossman, Masaharu Akiyama, Dharminder Chauhan, Teru Hideshima, Steven P. Treon, Nikhil C. Munshi, Paul G. Richardson, Kenneth C. Anderson
{"title":"Editorial Expression of Concern: Activation of NF-κB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications","authors":"Constantine S. Mitsiades, Nicholas Mitsiades, Vassiliki Poulaki, Robert Schlossman, Masaharu Akiyama, Dharminder Chauhan, Teru Hideshima, Steven P. Treon, Nikhil C. Munshi, Paul G. Richardson, Kenneth C. Anderson","doi":"10.1038/s41388-024-03217-8","DOIUrl":"10.1038/s41388-024-03217-8","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 4","pages":"269-269"},"PeriodicalIF":6.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03217-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lung cancer is the leading cause of cancer-related mortality globally. N6-methyladenosine (m6A) is the most abundant modification in mammalian mRNA and is involved in the biological regulation of tumors, including lung cancer. However, the role of m6A-related proteins, such as RNA-binding motif protein 15 (RBM15), in lung cancer progression remains largely unknown. Our study indicated that RBM15 is significantly overexpressed in lung adenocarcinoma, serving as an independent prognostic factor for poor outcomes and facilitating tumor cell proliferation and migration. RBM15 was markedly elevated in patients with EGFR mutations, correlating with a poorer prognosis, while it had negligible prognostic value in EGFR wild-type patients. As EGFR-tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with EGFR mutations, we subsequently determined that RBM15 drives osimertinib resistance via a novel mechanism: enhancing m6A modification of cwcv- and kazal-like domains proteoglycan 1 (SPOCK1) mRNA, promoting epithelial–mesenchymal transition-mediated osimertinib resistance through a bypass activation pathway. These findings were validated in osimertinib-resistant H1975 cells and organoids from patients with osimertinib-resistant lung adenocarcinoma. Furthermore, the RBM15–SPOCK1 axis was activated in drug-tolerant persister cells, indicating that early targeting of RBM15 during EGFR-TKI treatment could dramatically extend the patient response and benefit from TKI therapy. Our results emphasize the critical role of RBM15 in reversing EGFR-TKI resistance and propose it as a promising therapeutic target for prolonging TKI treatment benefits in patients with lung adenocarcinoma.
{"title":"RBM15 facilitates osimertinib resistance of lung adenocarcinoma through m6A-dependent epigenetic silencing of SPOCK1","authors":"Hongxiang Li, Yin Li, Xiaoxiao Zheng, Fangqian Chen, Shufen Zhang, Shuguang Xu, Yinyu Mu, Wei Shen, Jingtao Tong, Hang Chen, Zeyang Hu, Jiaheng Zhang, Keyue Qiu, Wei Chen, Xinghua Cheng, Guodong Xu","doi":"10.1038/s41388-024-03220-z","DOIUrl":"10.1038/s41388-024-03220-z","url":null,"abstract":"Lung cancer is the leading cause of cancer-related mortality globally. N6-methyladenosine (m6A) is the most abundant modification in mammalian mRNA and is involved in the biological regulation of tumors, including lung cancer. However, the role of m6A-related proteins, such as RNA-binding motif protein 15 (RBM15), in lung cancer progression remains largely unknown. Our study indicated that RBM15 is significantly overexpressed in lung adenocarcinoma, serving as an independent prognostic factor for poor outcomes and facilitating tumor cell proliferation and migration. RBM15 was markedly elevated in patients with EGFR mutations, correlating with a poorer prognosis, while it had negligible prognostic value in EGFR wild-type patients. As EGFR-tyrosine kinase inhibitors (TKIs) are the standard treatment for patients with EGFR mutations, we subsequently determined that RBM15 drives osimertinib resistance via a novel mechanism: enhancing m6A modification of cwcv- and kazal-like domains proteoglycan 1 (SPOCK1) mRNA, promoting epithelial–mesenchymal transition-mediated osimertinib resistance through a bypass activation pathway. These findings were validated in osimertinib-resistant H1975 cells and organoids from patients with osimertinib-resistant lung adenocarcinoma. Furthermore, the RBM15–SPOCK1 axis was activated in drug-tolerant persister cells, indicating that early targeting of RBM15 during EGFR-TKI treatment could dramatically extend the patient response and benefit from TKI therapy. Our results emphasize the critical role of RBM15 in reversing EGFR-TKI resistance and propose it as a promising therapeutic target for prolonging TKI treatment benefits in patients with lung adenocarcinoma.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 5","pages":"307-321"},"PeriodicalIF":6.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-10DOI: 10.1038/s41388-024-03218-7
Kara M. McNamara, Johanna C. Sierra, Yvonne L. Latour, Caroline V. Hawkins, Mohammad Asim, Kamery J. Williams, Daniel P. Barry, Margaret M. Allaman, Irene Zagol-Ikapitte, Paula B. Luis, Claus Schneider, Alberto G. Delgado, M. Blanca Piazuelo, Regina N. Tyree, Kate S. Carson, Yash A. Choksi, Lori A. Coburn, Alain P. Gobert, Keith T. Wilson
Helicobacter pylori is the primary cause of gastric cancer, and there is a need to discover new molecular targets for therapeutic intervention in H. pylori disease progression. We have previously shown that spermine oxidase (SMOX), the enzyme that catabolizes the back-conversion of the polyamine spermine to spermidine, is upregulated during infection and is associated with increased cancer risk in humans. We sought to determine the direct role of SMOX in gastric carcinogenesis during H. pylori infection. In this study, we demonstrate that transgenic FVB/N insulin-gastrin (INS-GAS) mice that develop gastric carcinoma with H. pylori infection were protected from cancer development with Smox deletion. RNA sequencing revealed that genes associated with the immune system and cancer were downregulated in the infected Smox–/– mice. Furthermore, there was a decrease in cell proliferation and DNA damage in infected Smox–/– animals. There was significant generation of adducts of the highly reactive electrophile acrolein, a byproduct of SMOX activity, in gastric tissues from H. pylori-infected humans and wild-type, but not Smox–/– mice. Genetic deletion of Smox in murine organoids or chemical inhibition of SMOX in human gastric epithelial cells significantly reduced generation of acrolein induced by H. pylori. Additionally, acrolein-induced DNA damage in gastric epithelial cells was ablated with the electrophile scavenger 2-hydroxybenzylamine (2-HOBA). Gastric acrolein adduct levels were attenuated in infected INS-GAS mice treated with 2-HOBA, which exhibit reduced gastric carcinoma. These findings implicate SMOX and acrolein in H. pylori-induced carcinogenesis, thus indicating their potential as therapeutic targets.
{"title":"Spermine oxidase promotes Helicobacter pylori-mediated gastric carcinogenesis through acrolein production","authors":"Kara M. McNamara, Johanna C. Sierra, Yvonne L. Latour, Caroline V. Hawkins, Mohammad Asim, Kamery J. Williams, Daniel P. Barry, Margaret M. Allaman, Irene Zagol-Ikapitte, Paula B. Luis, Claus Schneider, Alberto G. Delgado, M. Blanca Piazuelo, Regina N. Tyree, Kate S. Carson, Yash A. Choksi, Lori A. Coburn, Alain P. Gobert, Keith T. Wilson","doi":"10.1038/s41388-024-03218-7","DOIUrl":"10.1038/s41388-024-03218-7","url":null,"abstract":"Helicobacter pylori is the primary cause of gastric cancer, and there is a need to discover new molecular targets for therapeutic intervention in H. pylori disease progression. We have previously shown that spermine oxidase (SMOX), the enzyme that catabolizes the back-conversion of the polyamine spermine to spermidine, is upregulated during infection and is associated with increased cancer risk in humans. We sought to determine the direct role of SMOX in gastric carcinogenesis during H. pylori infection. In this study, we demonstrate that transgenic FVB/N insulin-gastrin (INS-GAS) mice that develop gastric carcinoma with H. pylori infection were protected from cancer development with Smox deletion. RNA sequencing revealed that genes associated with the immune system and cancer were downregulated in the infected Smox–/– mice. Furthermore, there was a decrease in cell proliferation and DNA damage in infected Smox–/– animals. There was significant generation of adducts of the highly reactive electrophile acrolein, a byproduct of SMOX activity, in gastric tissues from H. pylori-infected humans and wild-type, but not Smox–/– mice. Genetic deletion of Smox in murine organoids or chemical inhibition of SMOX in human gastric epithelial cells significantly reduced generation of acrolein induced by H. pylori. Additionally, acrolein-induced DNA damage in gastric epithelial cells was ablated with the electrophile scavenger 2-hydroxybenzylamine (2-HOBA). Gastric acrolein adduct levels were attenuated in infected INS-GAS mice treated with 2-HOBA, which exhibit reduced gastric carcinoma. These findings implicate SMOX and acrolein in H. pylori-induced carcinogenesis, thus indicating their potential as therapeutic targets.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 5","pages":"296-306"},"PeriodicalIF":6.9,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-09DOI: 10.1038/s41388-024-03211-0
Angelica Escoto, Ryan Hecksel, Chance Parkinson, Sara Crane, Benjamin Atwell, Shyanne King, Daniela Ortiz Chavez, Alison Jannuzi, Barbara Sands, Benjamin G. Bitler, Todd A. Fehniger, Andrew L. Paek, Megha Padi, Joyce Schroeder
Natural Killer (NK) cells can target and destroy cancer cells, yet tumor microenvironments typically suppress NK cell recruitment and cytotoxicity. The epidermal growth factor receptor (EGFR) is a potent oncogene that can activate survival, migration, and proliferation pathways, and clinical data suggests it may also play an immunomodulating role in cancers. Recent work has demonstrated a novel role for nuclear EGFR (nEGFR) in regulating transcriptional events unique from the kinase domain. Using a novel peptide therapeutic (cSNX1.3) that inhibits retrograde trafficking of EGFR and an EGFR nuclear localization mutant, we discovered that nEGFR suppresses NK cell recruitment and cytotoxicity. RNA-Seq analysis of breast cancer cells treated with cSNX1.3 or modified to lack a nuclear localization sequence (EGFRΔNLS) revealed the EGF-dependent induction of NK activating receptor ligands, while kinase inhibition by erlotinib did not impact these genes. NanoString analysis of tumor-bearing WAP-TGFα transgenic mice treated with cSNX1.3 demonstrated an increase in immune cell populations and activating genes. Additionally, immunohistochemistry confirmed an increase in NK cells upon cSNX1.3 treatment. Finally, cSNX1.3 treatment was found to enhance NK cell recruitment and cytotoxicity in vitro. Together, the data demonstrate a unique immunomodulatory role for nEGFR.
自然杀伤（NK）细胞可以靶向摧毁癌细胞，但肿瘤微环境通常会抑制 NK 细胞的招募和细胞毒性。表皮生长因子受体（EGFR）是一种强效致癌基因，可激活生存、迁移和增殖途径，临床数据表明它还可能在癌症中发挥免疫调节作用。最近的研究表明，核表皮生长因子受体（nEGFR）在调节与激酶结构域不同的转录事件中发挥着新的作用。我们利用一种抑制表皮生长因子受体逆向运输的新型多肽疗法（cSNX1.3）和表皮生长因子受体核定位突变体，发现 nEGFR 可抑制 NK 细胞的招募和细胞毒性。用cSNX1.3或经修饰缺失核定位序列（表皮生长因子受体ΔNLS）处理的乳腺癌细胞的RNA-Seq分析显示，表皮生长因子受体依赖性诱导NK激活受体配体，而厄洛替尼的激酶抑制对这些基因没有影响。对接受 cSNX1.3 治疗的肿瘤 WAP-TGFα 转基因小鼠进行的 NanoString 分析表明，免疫细胞群和活化基因有所增加。此外，免疫组化也证实了 cSNX1.3 治疗后 NK 细胞的增加。最后，cSNX1.3 还能增强体外 NK 细胞的招募和细胞毒性。这些数据共同证明了 nEGFR 的独特免疫调节作用。
{"title":"Nuclear EGFR in breast cancer suppresses NK cell recruitment and cytotoxicity","authors":"Angelica Escoto, Ryan Hecksel, Chance Parkinson, Sara Crane, Benjamin Atwell, Shyanne King, Daniela Ortiz Chavez, Alison Jannuzi, Barbara Sands, Benjamin G. Bitler, Todd A. Fehniger, Andrew L. Paek, Megha Padi, Joyce Schroeder","doi":"10.1038/s41388-024-03211-0","DOIUrl":"10.1038/s41388-024-03211-0","url":null,"abstract":"Natural Killer (NK) cells can target and destroy cancer cells, yet tumor microenvironments typically suppress NK cell recruitment and cytotoxicity. The epidermal growth factor receptor (EGFR) is a potent oncogene that can activate survival, migration, and proliferation pathways, and clinical data suggests it may also play an immunomodulating role in cancers. Recent work has demonstrated a novel role for nuclear EGFR (nEGFR) in regulating transcriptional events unique from the kinase domain. Using a novel peptide therapeutic (cSNX1.3) that inhibits retrograde trafficking of EGFR and an EGFR nuclear localization mutant, we discovered that nEGFR suppresses NK cell recruitment and cytotoxicity. RNA-Seq analysis of breast cancer cells treated with cSNX1.3 or modified to lack a nuclear localization sequence (EGFRΔNLS) revealed the EGF-dependent induction of NK activating receptor ligands, while kinase inhibition by erlotinib did not impact these genes. NanoString analysis of tumor-bearing WAP-TGFα transgenic mice treated with cSNX1.3 demonstrated an increase in immune cell populations and activating genes. Additionally, immunohistochemistry confirmed an increase in NK cells upon cSNX1.3 treatment. Finally, cSNX1.3 treatment was found to enhance NK cell recruitment and cytotoxicity in vitro. Together, the data demonstrate a unique immunomodulatory role for nEGFR.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 5","pages":"288-295"},"PeriodicalIF":6.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tyrosine kinase inhibitors (TKIs) are highly effective in the treatment of patients with chronic myeloid leukemia (CML), but fail to eliminate leukemia stem cells (LSCs), which can lead to disease relapse or progression. It is urgently need to identify the regulators specifically driving LSCs. In this study, we identified DEAD-box helicase 3 X-linked (DDX3X), a ubiquitously expressed RNA helicase, as a critical regulator for CML LSCs by using patient samples and BCR-ABL-driven CML mouse model. We found that DDX3X enhanced the survival, serially plating and long-term engraftment abilities of human primary CML CD34+ cells. Inhibition of DDX3X reduced leukemia burden, eradicated LSCs and extended the survival of CML mice. Mechanistically, we uncovered that DDX3X protein bound to 5′-Nucleotidase Domain Containing 2 (NT5DC2) mRNA and promoted its translation in CML cells. NT5DC2 was a functional mediator in DDX3X regulation of LSCs. Collectively, our findings provide new evidence for RNA helicase facilitating the translation of specific mRNA in LSCs. Targeting DDX3X may represent a promising therapeutic strategy for eradication of LSCs in CML patients.
{"title":"Targeting DDX3X eliminates leukemia stem cells in chronic myeloid leukemia by blocking NT5DC2 mRNA translation","authors":"Chen Duan, Xiaoying Lin, Waiyi Zou, Qi He, Fen Wei, Jingxuan Pan, Chang Liu, Yanli Jin","doi":"10.1038/s41388-024-03215-w","DOIUrl":"10.1038/s41388-024-03215-w","url":null,"abstract":"Tyrosine kinase inhibitors (TKIs) are highly effective in the treatment of patients with chronic myeloid leukemia (CML), but fail to eliminate leukemia stem cells (LSCs), which can lead to disease relapse or progression. It is urgently need to identify the regulators specifically driving LSCs. In this study, we identified DEAD-box helicase 3 X-linked (DDX3X), a ubiquitously expressed RNA helicase, as a critical regulator for CML LSCs by using patient samples and BCR-ABL-driven CML mouse model. We found that DDX3X enhanced the survival, serially plating and long-term engraftment abilities of human primary CML CD34+ cells. Inhibition of DDX3X reduced leukemia burden, eradicated LSCs and extended the survival of CML mice. Mechanistically, we uncovered that DDX3X protein bound to 5′-Nucleotidase Domain Containing 2 (NT5DC2) mRNA and promoted its translation in CML cells. NT5DC2 was a functional mediator in DDX3X regulation of LSCs. Collectively, our findings provide new evidence for RNA helicase facilitating the translation of specific mRNA in LSCs. Targeting DDX3X may represent a promising therapeutic strategy for eradication of LSCs in CML patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 4","pages":"241-254"},"PeriodicalIF":6.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03215-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1038/s41388-024-03207-w
Ming Wen, Yanfang Qiu, Meng Wang, Feiyu Tang, Wenfeng Hu, Yongwei Zhu, Wenchao Zhao, Wenzhen Hu, Zhuohang Chen, Yumei Duan, Anke Geng, Fengbo Tan, Yuqiang Li, Qian Pei, Haiping Pei, Zhiyong Mao, Ningbo Wu, Lunquan Sun, Rong Tan
The effectiveness of radiotherapy in colorectal cancer (CRC) relies on its ability to induce cell death via the generation of reactive oxygen species (ROS). However, genes responsible for mitigating oxidative stress can impede radiotherapy’s efficacy. In this study, we elucidate a significant association between the nucleolar protein Fibrillarin (FBL) and the oxidative stress response in CRC tumors. Our findings reveal elevated expression of FBL in colorectal cancer, which positively correlates with oxidative stress levels. Mechanistically, FBL demonstrates direct accumulation at DNA damage sites under the regulation of PARP1. Specifically, the N-terminal GAR domain of FBL is susceptible to PARylation by PARP1, enabling FBL to recognize PARylated proteins. The accumulation of damaged FBL plays a pivotal role in facilitating short-patched base excision repair by recruiting Ligase III and disassociating PCNA and FEN1. Moreover, tumors with heightened FBL expression exhibit reduced DNA damage levels but increased sensitivity to combined low-dose radiotherapy and olaparib treatment. This underscores the potential of leveraging PARP inhibitors to augment radiotherapy sensitivity in CRC cases characterized by elevated FBL expression, offering a promising therapeutic avenue.
放疗对结直肠癌（CRC）的疗效取决于其通过产生活性氧（ROS）诱导细胞死亡的能力。然而，负责减轻氧化应激的基因会阻碍放疗的疗效。在这项研究中，我们阐明了细胞核蛋白纤维蛋白（FBL）与癌症肿瘤氧化应激反应之间的重要关联。我们的研究结果表明，FBL在结直肠癌中的表达升高，与氧化应激水平呈正相关。从机理上讲，FBL在PARP1的调控下直接在DNA损伤位点聚集。具体来说，FBL 的 N 端 GAR 结构域易受 PARP1 的 PAR 化作用，从而使 FBL 能够识别 PAR 化蛋白。受损 FBL 的积累通过招募连接酶 III 和分解 PCNA 和 FEN1，在促进短斑块碱基切除修复中发挥了关键作用。此外，FBL表达增高的肿瘤DNA损伤水平降低，但对低剂量放疗和奥拉帕利联合治疗的敏感性增加。这凸显了利用PARP抑制剂提高FBL表达增高的CRC病例放疗敏感性的潜力，为治疗提供了一条前景广阔的途径。
{"title":"Enhancing low-dose radiotherapy efficacy with PARP inhibitors via FBL-mediated oxidative stress response in colorectal cancer","authors":"Ming Wen, Yanfang Qiu, Meng Wang, Feiyu Tang, Wenfeng Hu, Yongwei Zhu, Wenchao Zhao, Wenzhen Hu, Zhuohang Chen, Yumei Duan, Anke Geng, Fengbo Tan, Yuqiang Li, Qian Pei, Haiping Pei, Zhiyong Mao, Ningbo Wu, Lunquan Sun, Rong Tan","doi":"10.1038/s41388-024-03207-w","DOIUrl":"10.1038/s41388-024-03207-w","url":null,"abstract":"The effectiveness of radiotherapy in colorectal cancer (CRC) relies on its ability to induce cell death via the generation of reactive oxygen species (ROS). However, genes responsible for mitigating oxidative stress can impede radiotherapy’s efficacy. In this study, we elucidate a significant association between the nucleolar protein Fibrillarin (FBL) and the oxidative stress response in CRC tumors. Our findings reveal elevated expression of FBL in colorectal cancer, which positively correlates with oxidative stress levels. Mechanistically, FBL demonstrates direct accumulation at DNA damage sites under the regulation of PARP1. Specifically, the N-terminal GAR domain of FBL is susceptible to PARylation by PARP1, enabling FBL to recognize PARylated proteins. The accumulation of damaged FBL plays a pivotal role in facilitating short-patched base excision repair by recruiting Ligase III and disassociating PCNA and FEN1. Moreover, tumors with heightened FBL expression exhibit reduced DNA damage levels but increased sensitivity to combined low-dose radiotherapy and olaparib treatment. This underscores the potential of leveraging PARP inhibitors to augment radiotherapy sensitivity in CRC cases characterized by elevated FBL expression, offering a promising therapeutic avenue.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 4","pages":"228-240"},"PeriodicalIF":6.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03207-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1038/s41388-024-03202-1
Yuchun Niu, Yichun Tang, Feng Ma, Xuyang Zhou, Yi Chen, Yu Wang, Yue Xu, Lei Sun, Shaoqiang Liang, Jianqi Yang, Kai Wang, Fan Zhang, Shan Su, Linlang Guo
Small cell lung cancer (SCLC) is an aggressive form of lung cancer that often becomes resistant to chemotherapy. Understanding the molecular mechanisms of chemoresistance is crucial for identifying effective therapeutic targets. In this study, we used RNA-Seq to identify highly expressed molecules associated with chemoresistance. We also performed H3K27Ac and ATAC-Seq binding analyses to identify super-enhancers (SE) and their corresponding transcription factors. Both in vitro and in vivo experiments were conducted to examine the impact of these molecules and clinical samples were collected to establish their prognostic value. Our findings revealed elevated expression of MYCNOS, which exhibited chemoresistant properties in both in vitro and in vivo models of SCLC. We identified MYCNOS-SE as a significant SE in SCLC that regulates the distal target gene MYCNOS. This SE recruits transcription factors CTCF and KLF15 to regulate MYCNOS expression. Additionally, MYCNOS, an antisense of MYCN, was found to modulate chemotherapy sensitivity through the NOTCH pathway. This study highlights the significance of SE -regulated target genes as markers for chemoresistance in SCLC. Furthermore, it suggests that MYCNOS could serve as a predictor to identify patients who may benefit from NOTCH inhibitors. These findings provide valuable insights for future studies aimed at developing therapeutic strategies targeting these identified pathways.
{"title":"Super-enhancer MYCNOS-SE promotes chemoresistance in small cell lung cancer by recruiting transcription factors CTCF and KLF15","authors":"Yuchun Niu, Yichun Tang, Feng Ma, Xuyang Zhou, Yi Chen, Yu Wang, Yue Xu, Lei Sun, Shaoqiang Liang, Jianqi Yang, Kai Wang, Fan Zhang, Shan Su, Linlang Guo","doi":"10.1038/s41388-024-03202-1","DOIUrl":"10.1038/s41388-024-03202-1","url":null,"abstract":"Small cell lung cancer (SCLC) is an aggressive form of lung cancer that often becomes resistant to chemotherapy. Understanding the molecular mechanisms of chemoresistance is crucial for identifying effective therapeutic targets. In this study, we used RNA-Seq to identify highly expressed molecules associated with chemoresistance. We also performed H3K27Ac and ATAC-Seq binding analyses to identify super-enhancers (SE) and their corresponding transcription factors. Both in vitro and in vivo experiments were conducted to examine the impact of these molecules and clinical samples were collected to establish their prognostic value. Our findings revealed elevated expression of MYCNOS, which exhibited chemoresistant properties in both in vitro and in vivo models of SCLC. We identified MYCNOS-SE as a significant SE in SCLC that regulates the distal target gene MYCNOS. This SE recruits transcription factors CTCF and KLF15 to regulate MYCNOS expression. Additionally, MYCNOS, an antisense of MYCN, was found to modulate chemotherapy sensitivity through the NOTCH pathway. This study highlights the significance of SE -regulated target genes as markers for chemoresistance in SCLC. Furthermore, it suggests that MYCNOS could serve as a predictor to identify patients who may benefit from NOTCH inhibitors. These findings provide valuable insights for future studies aimed at developing therapeutic strategies targeting these identified pathways.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 4","pages":"255-268"},"PeriodicalIF":6.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03202-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1038/s41388-024-03214-x
S. Fulda, K. -M. Debatin
{"title":"Editorial Expression of Concern: 5-Aza-2′-deoxycytidine and IFN-γ cooperate to sensitize for TRAIL-induced apoptosis by upregulating caspase-8","authors":"S. Fulda, K. -M. Debatin","doi":"10.1038/s41388-024-03214-x","DOIUrl":"10.1038/s41388-024-03214-x","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"43 49","pages":"3617-3617"},"PeriodicalIF":6.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03214-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1038/s41388-024-03203-0
Verónica A. García-García, Josefa P. Alameda, M. Jesús Fernández-Aceñero, Manuel Navarro, Ramón García-Escudero, Angustias Page, Raúl Mateo-Gallego, Jesús M. Paramio, Ángel Ramírez, Rosa A. García-Fernández, Ana Bravo, M. Llanos Casanova
IKKα is known as an essential protein for skin homeostasis. However, the lack of suitable models to investigate its functions in the skin has led to IKKα being mistakenly considered as a suppressor of non-melanoma skin cancer (NMSC) development. In this study, using our previously generated transgenic mouse models expressing exogenous IKKα in the cytoplasm (C-IKKα mice) or in the nucleus (N-IKKα mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKα differently regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, and for the cutaneous inflammatory response. In addition, each type of IKKα-transgenic mice shows different predisposition to the development of spontaneous NMSC. Specifically, N-IKKα mice display an atrophic epidermis with exacerbated terminal differentiation, signs of premature skin aging, premalignant lesions, and develop squamous cell carcinomas (SCCs). Conversely, C-IKKα mice, whose keratinocytes are nearly devoid of endogenous nuclear IKKα, do not develop skin SCCs, although they exhibit hyperplastic skin with deficiencies in terminal epidermal differentiation, chronic cutaneous inflammation, and constitutive activation of STAT-3 and NF-κB signaling pathways. Altogether, our data demonstrate that alterations in the localization of IKKα in the nucleus or cytoplasm of keratinocytes cause opposite skin changes and differentially predispose to the growth of skin SCCs.
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