{"title":"m6A-Mediated Induction of 7-Dehydrocholesterol Reductase Stimulates Cholesterol Synthesis and cAMP Signaling to Promote Bladder Cancer Metastasis.","authors":"Youmiao Zeng, Yongbo Luo, Keyuan Zhao, Sheng Liu, Kaiwen Wu, Yudong Wu, Kaixuan Du, Wenbang Pan, Yiheng Dai, Yuanhao Liu, Mengda Ren, Fengyan Tian, Lijie Zhou, Chaohui Gu","doi":"10.1158/0008-5472.CAN-23-3703","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-3703","url":null,"abstract":"<p><p>Dysregulation of cholesterol homeostasis occurs in multiple types of tumors and promotes cancer progression. Investigating the specific processes that induce abnormal cholesterol metabolism could identify therapeutic targets to improve cancer treatment. In this investigation, we observed upregulation of 7-dehydrocholesterol reductase (DHCR7), a vital enzyme involved in the synthesis of cholesterol, within bladder cancer (BC) tissues in comparison to normal tissues, which was correlated with increased BC metastasis. Increased expression of DHCR7 in BC was attributed to decreased mRNA degradation mediated by YTHDF2. Loss or inhibition of DHCR7 reduced BC cell invasion in vitro and metastasis in vivo. Mechanistically, DHCR7 promoted BC metastasis by activating the cAMP/PKA/FAK pathway. Specifically, DHCR7 increased cAMP levels by elevating cholesterol content in lipid rafts, thereby facilitating the transduction of signaling pathways mediated by cAMP receptors. DHCR7 additionally enhanced the cAMP signaling pathway by reducing the concentration of 7-DHC and promoting the transcription of the G protein-coupled receptor GIPR. Overall, these findings demonstrate that DHCR7 plays an important role in BC invasion and metastasis by modulating cholesterol synthesis and cAMP signaling. Furthermore, inhibition of DHCR7 shows promise as a viable therapeutic strategy for suppressing BC invasion and metastasis.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Arginine methylation of DDX3 by PRMT1 mediates mitochondrial homeostasis to promote breast cancer metastasis.","authors":"Wen-Jing Hsu, Ming-Chen Chiang, Yi-Chun Chao, Yu-Chu Chang, Ming-Chien Hsu, Chu-Hung Chung, I-Lin Tsai, Cheng-Ying Chu, Han-Chung Wu, Ching-Chieh Yang, Chi-Ching Lee, Cheng-Wei Lin","doi":"10.1158/0008-5472.CAN-23-3829","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-3829","url":null,"abstract":"<p><p>Dysregulated mitochondrial dynamics and metabolism play important roles in tumorigenesis. Metastasizing tumor cells predominantly utilize mitochondrial metabolism, and regulators of metabolic reprogramming may provide reliable biomarkers for diagnosing cancer metastasis. Here, we identified a PRMT1-DDX3 axis that promotes breast cancer metastasis by coordinating mitochondrial biogenesis and mitophagy to ensure mitochondrial quality control. Mechanistically, PRMT1 induces arginine methylation of DDX3, which enhances its protein stability and prevents proteasomal degradation. DDX3 mediates mitochondrial homeostasis by translocating to mitochondria where it facilitates PINK1 translation in response to mitochondrial stress. Inhibition of DDX3 suppresses mitochondrial biogenesis and mitophagy, resulting in diminished cancer stemness and metastatic properties. Overall, this study uncovers a mechanism by which the PRMT1-DDX3 axis regulates mitochondrial homeostasis to support breast cancer metastasis, suggesting strategies for targeting metabolic vulnerabilities to treat metastatic breast cancer.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2024-07-22DOI: 10.1158/0008-5472.CAN-23-3419
Camino Bermejo-Rodriguez, Joaquín Araos Henríquez, Giuseppina Caligiuri, Sara Pinto Teles, Youngkyu Park, Anthony Evans, Lawrence N Barrera, Albrecht Neesse, Robert Grutzmann, Daniela Aust, Petra Rümmele, Thomas Knösel, Masako Narita, Masashi Narita, Fiona Campbell, Daniel Öhlund, Christian Pilarsky, Lukas E Dow, Patrick O Humbert, Giulia Biffi, David A Tuveson, Pedro A Perez-Mancera
{"title":"Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis.","authors":"Camino Bermejo-Rodriguez, Joaquín Araos Henríquez, Giuseppina Caligiuri, Sara Pinto Teles, Youngkyu Park, Anthony Evans, Lawrence N Barrera, Albrecht Neesse, Robert Grutzmann, Daniela Aust, Petra Rümmele, Thomas Knösel, Masako Narita, Masashi Narita, Fiona Campbell, Daniel Öhlund, Christian Pilarsky, Lukas E Dow, Patrick O Humbert, Giulia Biffi, David A Tuveson, Pedro A Perez-Mancera","doi":"10.1158/0008-5472.CAN-23-3419","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-3419","url":null,"abstract":"<p><p>Perturbation of cell polarity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) progression. Scribble (SCRIB) is a well characterized polarity regulator that has diverse roles in the pathogenesis of human neoplasms. To investigate the impact of SCRIB deficiency on PDAC development and progression, Scrib was genetically ablated in well-established mouse models of PDAC. Scrib loss in combination with KrasG12D did not influence development of pancreatic intraepithelial neoplasms (PanIN) in mice. However, Scrib deletion cooperated with KrasG12D and concomitant Trp53 heterozygous deletion to promote invasive PDAC and metastatic dissemination, leading to reduced overall survival. Immunohistochemical and transcriptome analyses revealed that Scrib-null tumors display a pronounced reduction of collagen content and cancer associated fibroblast (CAF) abundance. Mechanistically, interleukin 1α (IL1α) levels were reduced in Scrib deficient tumors, and Scrib knockdown downregulated IL1α in mouse PDAC organoids (mPDOs), which impaired CAF activation. Furthermore, Scrib loss increased YAP activation in mPDOs and established PDAC cell lines, enhancing cell survival. Clinically, SCRIB expression was decreased in human PDAC, and SCRIB mislocalization was associated with poorer patient outcome. These results indicate that SCRIB deficiency enhances cancer cell survival and remodels the tumor microenvironment to accelerate PDAC development and progression, establishing the tumor suppressor function of SCRIB in advanced pancreatic cancer.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2024-07-22DOI: 10.1158/0008-5472.CAN-23-2558
Katrina M Piemonte, Natasha N Ingles, Kristen L Weber Bonk, Mitchell J Valentine, Parth R Majmudar, Salendra Singh, Ruth A Keri
{"title":"Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer.","authors":"Katrina M Piemonte, Natasha N Ingles, Kristen L Weber Bonk, Mitchell J Valentine, Parth R Majmudar, Salendra Singh, Ruth A Keri","doi":"10.1158/0008-5472.CAN-23-2558","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-2558","url":null,"abstract":"<p><p>Clinical trials examining broad-spectrum Src family kinase (SFK) inhibitors revealed significant dose-limiting toxicities, preventing advancement for solid tumors. SFKs are functionally heterogeneous, thus targeting individual members is a potential strategy to elicit anti-tumor efficacy while avoiding toxicity. Here, we identified that YES1 is the most highly overexpressed SFK in triple negative breast cancer (TNBC) and is associated with poor patient outcomes. Disrupting YES1, genetically or pharmacologically, induced aberrant mitosis, centrosome amplification, multi-polar spindles, and chromosomal instability (CIN). Mechanistically, YES1 sustained FOXM1 protein levels and elevated expression of FOXM1 target genes that control centrosome function and are essential for effective and accurate mitotic progression. In both in vitro and in vivo TNBC models, YES1 suppression potentiated the efficacy of taxanes, cornerstone drugs for TNBC that require elevated CIN for efficacy. Clinically, elevated expression of YES1 was associated with worse overall survival of TNBC patients treated with taxane and anthracycline combination regimens. Together, this study demonstrates that YES1 is an essential regulator of genome stability in TNBC that can be leveraged to improve taxane efficacy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"FANCI Inhibition Induces PARP1 Redistribution to Enhance the Efficacy of PARP Inhibitors in Breast Cancer.","authors":"Yu-Zhou Huang, Ming-Yi Sang, Pei-Wen Xi, Ruo-Xi Xu, Meng-Yuan Cai, Zi-Wen Wang, Jianyi Zhao, Yi-Han Li, Ji-Fu Wei, Qiang Ding","doi":"10.1158/0008-5472.CAN-23-2738","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-2738","url":null,"abstract":"<p><p>Breast cancer is a global public health concern with high mortality rates, necessitating the development of innovative treatment strategies. PARP inhibitors have shown efficacy in certain patient populations, but their application is largely limited to cancers with homologous recombination deficiency. Here, we identified the suppression of FANCI as a therapeutic strategy to enhance the efficacy of PARP inhibitors in breast cancer. Elevated FANCI expression in breast cancer was associated with poor prognosis and increased cell proliferation and migration. FANCI interacted with PARP1, and suppressing FANCI limited the nuclear localization and functionality of PARP1. Importantly, FANCI inhibition sensitized breast cancer cells to the PARP inhibitor talazoparib in the absence of BRCA mutations. Additionally, the CDK4/6 inhibitor palbociclib enhanced the sensitivity of breast cancer cells to talazoparib through FANCI inhibition. These findings highlight the potential of targeting FANCI to enhance the efficacy of PARP inhibitors in treating breast cancer.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2024-07-18DOI: 10.1158/0008-5472.CAN-23-4062
Songyi Liu, Chunlin Lin, Xiang Lin, Penghang Lin, Ruofan He, Xiaoyu Pan, Yan Lin, Jianxin Ye, Guangwei Zhu
{"title":"NAT10 Phase Separation Regulates YTHDF1 Splicing to Promote Gastric Cancer Progression.","authors":"Songyi Liu, Chunlin Lin, Xiang Lin, Penghang Lin, Ruofan He, Xiaoyu Pan, Yan Lin, Jianxin Ye, Guangwei Zhu","doi":"10.1158/0008-5472.CAN-23-4062","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-4062","url":null,"abstract":"<p><p>Gastric cancer (GC) is an aggressive malignancy with poor patient outcomes. NAT10 is an acetyltransferase that has been reported to contribute to GC progression. In-depth investigation into the underlying molecular mechanisms driven by NAT10 could help identify therapeutic targets to improve GC treatment. Here, we found that NAT10 forms condensates to regulate RNA dynamics and promote GC progression. In GC patient samples, elevated NAT10 expression correlated with an unfavorable prognosis, advanced disease stage, and metastasis. NAT10 enhanced proliferation, migration, and invasion of GC cells, supported growth of patient-derived organoids, and accelerated tumor development. A C-terminal intrinsically disordered region mediated liquid-liquid phase separation (LLPS) of NAT10 and was essential for its tumor-promoting function in GC. Moreover, NAT10 interacted with the splicing factor SRSF2, leading to its acetylation and increased stability. Acetylated SRSF2 directly bound to the pre-mRNA of the m6A reader YTHDF1, resulting in enhanced YTHDF1 exon 4 skipping and upregulation of a short YTHDF1 transcript that could stimulate GC cell proliferation and migration. Furthermore, YTHDF1 exon 4 skipping correlated with NAT10 and SRSF2 expression and was associated with a more aggressive phenotype in GC patient samples. Together, this study uncovers the role of NAT10 LLPS in modulating YTHDF1 splicing through SRSF2 acetylation to drive GC progression, providing insights into the oncogenic mechanism of NAT10.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2024-07-18DOI: 10.1158/0008-5472.CAN-23-3560
Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh V Dharia, Ashleigh Meyer, Lucy A Merickel, Delan Khalid, Sebastian Scheich, Bjorn Haupl, Louis M Staudt, Thomas Oellerich, Kimberly Stegmaier
{"title":"Targeting the Sodium-Potassium Pump as a Therapeutic Strategy in Acute Myeloid Leukemia.","authors":"Constanze Schneider, Hermes Spaink, Gabriela Alexe, Neekesh V Dharia, Ashleigh Meyer, Lucy A Merickel, Delan Khalid, Sebastian Scheich, Bjorn Haupl, Louis M Staudt, Thomas Oellerich, Kimberly Stegmaier","doi":"10.1158/0008-5472.CAN-23-3560","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-3560","url":null,"abstract":"<p><p>Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships, and gene expression in cancer models. Here, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the beta subunit of the sodium-potassium pump (Na/K-ATP pump), interacts with the alpha subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3's paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells both through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. ATP1B3 is thus a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2024-07-18DOI: 10.1158/0008-5472.CAN-23-4054
Maria E Gonzalez, Bryce Brophy, Ahmad Eido, Adele E Leonetti, Sabra I Djomehri, Giuseppina Augimeri, Nicholas J Carruthers, Raymond G Cavalcante, Francesca Giordano, Sebastiano Andò, Alexey I Nesvizhskii, Eric R Fearon, Celina G Kleer
{"title":"CCN6 suppresses metaplastic breast carcinoma by antagonizing WNT/β-catenin signaling to inhibit EZH2-driven EMT.","authors":"Maria E Gonzalez, Bryce Brophy, Ahmad Eido, Adele E Leonetti, Sabra I Djomehri, Giuseppina Augimeri, Nicholas J Carruthers, Raymond G Cavalcante, Francesca Giordano, Sebastiano Andò, Alexey I Nesvizhskii, Eric R Fearon, Celina G Kleer","doi":"10.1158/0008-5472.CAN-23-4054","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-4054","url":null,"abstract":"<p><p>Metaplastic breast carcinomas (mBrCAs) are a highly aggressive subtype of triple negative breast cancer (TNBC) with histological evidence of epithelial to mesenchymal transition (EMT) and aberrant differentiation. Inactivation of the tumor suppressor gene CCN6 (also known as WISP3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle mBrCAs with EMT. Elucidation of the precise mechanistic details of how CCN6 acts as a tumor suppressor in mBrCA could help identify improved treatment strategies. Here, we showed that CCN6 interacts with the Wnt receptor FZD8 and co-receptor LRP6 on mBrCA cells to antagonize Wnt-induced activation of β-catenin/TCF-mediated transcription. The histone methyltransferase EZH2 was identified as a β-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibiting Wnt/β-catenin/TCF signaling in Ccn6-KO mBrCa cells led to reduced EZH2 expression, decreased histone H3 lysine 27 trimethylation, and deregulation of specific target genes. Pharmacological inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo. Low CCN6 is significantly associated with activated β-catenin and high EZH2 in human spindle mBrCAs compared to other subtypes. Collectively, these findings establish CCN6 as a key negative regulator of a β-catenin/TCF-EZH2 axis and highlight inhibition of β-catenin or EZH2 as a potential therapeutic approach for patients with spindle mBrCAs.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2024-07-18DOI: 10.1158/0008-5472.CAN-24-0970
Alissandra L Hillis, Timothy D Martin, Haley E Manchester, Jenny Högström, Na Zhang, Emmalyn Lecky, Nina Kozlova, Jonah Lee, Nicole S Persky, David E Root, Myles Brown, Karen Cichowski, Stephen J Elledge, Taru Muranen, David A Fruman, Simon T Barry, John G Clohessy, Ralitsa R Madsen, Alex Toker
{"title":"Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.","authors":"Alissandra L Hillis, Timothy D Martin, Haley E Manchester, Jenny Högström, Na Zhang, Emmalyn Lecky, Nina Kozlova, Jonah Lee, Nicole S Persky, David E Root, Myles Brown, Karen Cichowski, Stephen J Elledge, Taru Muranen, David A Fruman, Simon T Barry, John G Clohessy, Ralitsa R Madsen, Alex Toker","doi":"10.1158/0008-5472.CAN-24-0970","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-0970","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro, in mouse TNBC xenografts and in patient-derived, estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. .</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2024-07-18DOI: 10.1158/0008-5472.CAN-24-0254
Jianqiang Yang, Fanghui Chen, Liwei Lang, Fan Yang, Zhenzhen Fu, Juan Martínez, Amber Cho, Nabil F Saba, Yong Teng
{"title":"Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer.","authors":"Jianqiang Yang, Fanghui Chen, Liwei Lang, Fan Yang, Zhenzhen Fu, Juan Martínez, Amber Cho, Nabil F Saba, Yong Teng","doi":"10.1158/0008-5472.CAN-24-0254","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-0254","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) is addicted to glutaminolysis. Targeting this metabolic dependency has emerged as a potential therapeutic approach for HNSCC. Here, we conducted a bioinformatic analysis of the TCGA HNSCC cohort that revealed a robust correlation between expression of c-Myc and GLS1, which catalyzes the first step in glutaminolysis. Intriguingly, disruption of GLS1 signaling in HNSCC cells by genetic depletion or CB-839 treatment resulted in a reduction in c-Myc protein stability via a USP1-dependent ubiquitin-proteasome pathway. On the other hand, c-Myc directly binds to the promoter region of GLS1 and upregulates its transcription. Notably, the GLS1-c-Myc pathway enhanced ACC-dependent SLUG acetylation, prompting cancer cell invasion and metastasis. Thus, the GLS1-c-Myc axis emerged as a positive feedback loop critical for driving the aggressiveness of HNSCC. Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared to either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for HNSCC patients, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":12.5,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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