Cancer letters最新文献_第10页

YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer 以 YBX1 为治疗靶点，抑制 LRP1-β-catenin-RRM1 轴，克服胰腺癌对吉西他滨的耐药性。

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-30 DOI: 10.1016/j.canlet.2024.217197

Borui Li , Faliang Xing , Jingyi Wang , Xiaohong Wang , Chenjie Zhou , Guixiong Fan , Qifeng Zhuo , Shunrong Ji , Xianjun Yu , Xiaowu Xu , Yi Qin , Zheng Li

{"title":"YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer","authors":"Borui Li , Faliang Xing , Jingyi Wang , Xiaohong Wang , Chenjie Zhou , Guixiong Fan , Qifeng Zhuo , Shunrong Ji , Xianjun Yu , Xiaowu Xu , Yi Qin , Zheng Li","doi":"10.1016/j.canlet.2024.217197","DOIUrl":"10.1016/j.canlet.2024.217197","url":null,"abstract":"<div><p>Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10 % 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic cancer.</p></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"602 ","pages":"Article 217197"},"PeriodicalIF":9.1,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304383524005925/pdfft?md5=dab68ebe7fcaba92cb6f561195b568a1&pid=1-s2.0-S0304383524005925-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104698","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}

引用次数: 0

MAZ promotes thyroid cancer progression by driving transcriptional reprogram and enhancing ERK1/2 activation MAZ通过驱动转录重编程和增强ERK1/2激活来促进甲状腺癌的进展。

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-27 DOI: 10.1016/j.canlet.2024.217201

Jiajia Zeng , Long Zhang , Linying Huang , Xinyuan Yu , Linyu Han , Yanxiu Zheng , Teng Wang , Nasha Zhang , Ming Yang

{"title":"MAZ promotes thyroid cancer progression by driving transcriptional reprogram and enhancing ERK1/2 activation","authors":"Jiajia Zeng , Long Zhang , Linying Huang , Xinyuan Yu , Linyu Han , Yanxiu Zheng , Teng Wang , Nasha Zhang , Ming Yang","doi":"10.1016/j.canlet.2024.217201","DOIUrl":"10.1016/j.canlet.2024.217201","url":null,"abstract":"<div><p>Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancies worldwide. Oncogenic transcription factors (TFs) drive transcriptional reprogramming and tumorigenesis. The myc-associated zinc finger protein (MAZ) is one of the Myc family TFs. The role of MAZ in PTC pathogenesis is still largely unknown. Here, we report that <em>MAZ</em> profoundly promotes proliferation of PTC cells <em>ex vivo</em> and <em>in vivo</em> through activating MAPK signaling. We firstly profiled gene expression of PTC cells after silencing of <em>MAZ</em>. <em>BRAF</em>, <em>KRAS</em> and <em>LOC547</em> were identified as important target genes of TF MAZ. In particular, TF MAZ bound to the promoters of <em>BRAF</em> or <em>KRAS</em> and significantly increased their transcription and expression levels. Meanwhile, MAZ could noticeably elevate <em>LOC547</em> transcription and expression as a TF. High levels of LOC547 relocated ACTN4 protein from the nucleus to the cytosol, improved protein-protein interactions between ACTN4 and EGFR in the cytosol, enhanced ERK1/2 phosphorylation, activated the MAPK signaling and, thus, promoted PTC progression. Our data identify a previously underappreciated MAZ-controlled transcriptional reprogram and ERK1/2 activation via <em>BRAF</em>, <em>KRAS</em> and <em>LOC547</em>. Our data illustrate that activation of the MAZ-controlled axis promotes thyroid tumorigenesis. These insights would advance our knowledge of the role of TFs in cancer development and highlight the potential of TFs as future targets for treatments against cancers.</p></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"602 ","pages":"Article 217201"},"PeriodicalIF":9.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092251","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}

引用次数: 0

Novel SARS-CoV-2 inhibition properties of the anti-cancer Kang Guan Recipe herbal formula 抗癌中药配方《康冠方》的新型 SARS-CoV-2 抑制特性

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-27 DOI: 10.1016/j.canlet.2024.217198

Wei-Jan Wang , Hsuan-Ting Tang , Shi-Chen Ou , Wan-Jou Shen , Chung-Yu Chen , Yi-Chuan Li , Sui-Yuan Chang , Wei-Chao Chang , Po-Ren Hsueh , Sheng-Teng Huang , Mien-Chie Hung

{"title":"Novel SARS-CoV-2 inhibition properties of the anti-cancer Kang Guan Recipe herbal formula","authors":"Wei-Jan Wang , Hsuan-Ting Tang , Shi-Chen Ou , Wan-Jou Shen , Chung-Yu Chen , Yi-Chuan Li , Sui-Yuan Chang , Wei-Chao Chang , Po-Ren Hsueh , Sheng-Teng Huang , Mien-Chie Hung","doi":"10.1016/j.canlet.2024.217198","DOIUrl":"10.1016/j.canlet.2024.217198","url":null,"abstract":"<div><div>The ongoing COVID-19 pandemic is a persistent challenge, with continued breakthrough infections despite vaccination efforts. This has spurred interest in alternative preventive measures, including dietary and herbal interventions. Previous research has demonstrated that herbal medicines can not only inhibit cancer progression but also combat viral infections, including COVID-19 by targeting SARS-CoV-2, indicating a multifaceted potential to address both viruses and cancer. Here, we found that the Kang Guan Recipe (KGR), a novel herbal medicine formula, associates with potent inhibition activity against the SARS-CoV-2 viral infection. We demonstrate that KGR exhibits inhibitory activity against several SARS-CoV-2 variants of concern (VOCs). Mechanistically, we found that KGR can block the interaction of the viral spike and human angiotensin-converting enzyme 2 (ACE2). Furthermore, we assessed the inhibitory effect of KGR on SARS-CoV-2 viral entry in vivo, observing that serum samples from healthy human subjects having taken KGR exhibited suppressive activity against SARS-CoV-2 variants. Our investigation provides valuable insights into the potential of KGR as a novel herbal-based preventive and therapeutic strategy against COVID-19.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"604 ","pages":"Article 217198"},"PeriodicalIF":9.1,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092250","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}

引用次数: 0

Fibrillarin reprograms glucose metabolism by driving the enhancer-mediated transcription of PFKFB4 in liver cancer 纤溶肝素通过驱动肝癌中 PFKFB4 的增强子介导转录重编程葡萄糖代谢

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-23 DOI: 10.1016/j.canlet.2024.217190

Yizhe Liu , Qili Shi , Yanfang Liu , Xinrong Li , Zhen Wang , Shenglin Huang , Zhiao Chen , Xianghuo He

{"title":"Fibrillarin reprograms glucose metabolism by driving the enhancer-mediated transcription of PFKFB4 in liver cancer","authors":"Yizhe Liu , Qili Shi , Yanfang Liu , Xinrong Li , Zhen Wang , Shenglin Huang , Zhiao Chen , Xianghuo He","doi":"10.1016/j.canlet.2024.217190","DOIUrl":"10.1016/j.canlet.2024.217190","url":null,"abstract":"<div><p>DNA- and RNA-binding proteins (DRBPs) are versatile proteins capable of binding to both DNA and RNA molecules. In this study, we identified fibrillarin (FBL) as a key DRBP that is upregulated in liver cancer tissues vs. normal tissues and is correlated with patient prognosis. FBL promotes the proliferation of liver cancer cells both in vitro and in vivo. Mechanistically, FBL interacts with the transcription factor KHSRP, thereby regulating the expression of genes involved in glucose metabolism and leading to the reprogramming of glucose metabolism. Specifically, FBL and KHSRP work together to transcriptionally activate the glycolytic enzyme PFKFB4 by co-occupying enhancer and promoter elements, thereby further promoting liver cancer growth. Collectively, these findings provide compelling evidence highlighting the role of FBL as a transcriptional regulator in liver cancer cells, working in conjunction with KHSRP. The FBL/KHSRP-PFKFB4 regulatory axis holds potential as both a prognostic indicator and a therapeutic target for liver cancer.</p></div><div><h3>Significance</h3><p>A novel role of FBL in the transcriptional activation of PFKFB4, leading to glucose metabolism reprogramming in liver cancer.</p></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"602 ","pages":"Article 217190"},"PeriodicalIF":9.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304383524005858/pdfft?md5=daa34b5b83d0468cee76e7cae846cf8a&pid=1-s2.0-S0304383524005858-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055047","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}

引用次数: 0

RNA-binding motif protein 28 enhances angiogenesis by improving STAT3 translation in hepatocellular carcinoma RNA 结合基调蛋白 28 通过改善肝细胞癌中 STAT3 的翻译促进血管生成。

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-22 DOI: 10.1016/j.canlet.2024.217191

Hexu Han , Yin Yuan , Caiying Li , Lei Liu , Hong Yu , Gaohua Han , Qiang Wang , Mei Lin , Junxing Huang

{"title":"RNA-binding motif protein 28 enhances angiogenesis by improving STAT3 translation in hepatocellular carcinoma","authors":"Hexu Han , Yin Yuan , Caiying Li , Lei Liu , Hong Yu , Gaohua Han , Qiang Wang , Mei Lin , Junxing Huang","doi":"10.1016/j.canlet.2024.217191","DOIUrl":"10.1016/j.canlet.2024.217191","url":null,"abstract":"<div><p>Hepatocellular carcinoma (HCC) is a prevalent malignant tumor characterized by extensive angiogenesis. However, the underlying mechanisms of HCC pathogenesis remain unclear. Previous studies have shown that RNA-binding proteins (RBPs) are implicated in HCC pathogenesis. In this study, we observed that increased RBM28 expression in HCC tissues was positively correlated with tumor microvascular density and negatively correlated with patient prognosis. Overexpression of RBM28 in HCC cells promoted tubule formation in human umbilical vein endothelial cells, whereas inhibition of RBM28 had the opposite effect, furthermore, the role of RBM28 in the progression of HCC was assessed using transgenic mouse models and chemically induced HCC models. We used various molecular assays and high-throughput detection methods to evaluate the role of RBM28 in promoting angiogenesis in HCC. Increased RBM28 expression in HCC directly binds to STAT3 mRNA, recruiting EIF4E to increase STAT3 expression and enhancing the secretion and expression of vascular endothelial growth factor A; consequently, promoting neovascularization in HCC. The potential of RBM28 as a viable diagnostic and therapeutic target for HCC was assessed using multi-cohort clinical samples and animal models. In summary, our results provide insights into the pathogenesis, clinical diagnosis, and treatment of HCC.</p></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"604 ","pages":"Article 217191"},"PeriodicalIF":9.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055048","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}

引用次数: 0

NBS1 lactylation and damaged DNA repair NBS1 乳化和受损 DNA 修复

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-22 DOI: 10.1016/j.canlet.2024.217128

H Phillip Koeffler

引用次数: 0

6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells 6-磷酸葡萄糖酸脱氢酶通过抑制肺腺癌细胞的 AMPK 通路促进糖酵解和脂肪酸合成

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-22 DOI: 10.1016/j.canlet.2024.217177

Jun Wu , Yong Chen , Hui Zou , Kaiyue Xu , Jiaqi Hou , Mengmeng Wang , Shuyu Tian , Mingjun Gao , Qinglin Ren , Chao Sun , Shichun Lu , Qiang Wang , Yusheng Shu , Shouyu Wang , Xiaolin Wang

{"title":"6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells","authors":"Jun Wu , Yong Chen , Hui Zou , Kaiyue Xu , Jiaqi Hou , Mengmeng Wang , Shuyu Tian , Mingjun Gao , Qinglin Ren , Chao Sun , Shichun Lu , Qiang Wang , Yusheng Shu , Shouyu Wang , Xiaolin Wang","doi":"10.1016/j.canlet.2024.217177","DOIUrl":"10.1016/j.canlet.2024.217177","url":null,"abstract":"<div><p>Abnormal metabolism has emerged as a prominent hallmark of cancer and plays a pivotal role in carcinogenesis and progression of lung adenocarcinoma (LUAD). In this study, single-cell sequencing revealed that the metabolic enzyme 6-phosphogluconate dehydrogenase (PGD), which is a critical regulator of the pentose phosphate pathway (PPP), is significantly upregulated in the malignant epithelial cell subpopulation during malignant progression. However, the precise functional significance of PGD in LUAD and its underlying mechanisms remain elusive. Through the integration of TCGA database analysis and LUAD tissue microarray data, it was found that PGD expression was significantly upregulated in LUAD and closely correlated with a poor prognosis in LUAD patients. Moreover, in vitro and in vivo analyses demonstrated that PGD knockout and inhibition of its activity mitigated the proliferation, migration, and invasion of LUAD cells. Mechanistically, immunoprecipitation-mass spectrometry (IP-MS) revealed for the first time that IQGAP1 is a robust novel interacting protein of PGD. PGD decreased p-AMPK levels by competitively interacting with the IQ domain of the known AMPKα binding partner IQGAP1, which promoted glycolysis and fatty acid synthesis in LUAD cells. Furthermore, we demonstrated that the combination of Physcion (a PGD-specific inhibitor) and metformin (an AMPK agonist) could inhibit tumor growth more effectively both in vivo and in vitro. Collectively, these findings suggest that PGD is a potential prognostic biomarker and therapeutic target for LUAD.</p></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"601 ","pages":"Article 217177"},"PeriodicalIF":9.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S030438352400572X/pdfft?md5=e0cd63779b18fb2cc3dc1b3ad8f2c58f&pid=1-s2.0-S030438352400572X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046410","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}

引用次数: 0

Blockade of the lncRNA-PART1-PHB2 axis confers resistance to PARP inhibitor and promotes cellular senescence in ovarian cancer 阻断lncRNA-PART1-PHB2轴可使卵巢癌患者对PARP抑制剂产生抗药性并促进细胞衰老。

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-22 DOI: 10.1016/j.canlet.2024.217192

Huan Wu , Chenggong Sun , Wenyu Cao , Qiuli Teng , Xinyue Ma , Helgi B. Schiöth , Ruifen Dong , Qing Zhang , Beihua Kong

{"title":"Blockade of the lncRNA-PART1-PHB2 axis confers resistance to PARP inhibitor and promotes cellular senescence in ovarian cancer","authors":"Huan Wu , Chenggong Sun , Wenyu Cao , Qiuli Teng , Xinyue Ma , Helgi B. Schiöth , Ruifen Dong , Qing Zhang , Beihua Kong","doi":"10.1016/j.canlet.2024.217192","DOIUrl":"10.1016/j.canlet.2024.217192","url":null,"abstract":"<div><p>PARPi is currently the most important breakthrough in the treatment of ovarian cancer in decades, and it has been integrated into the initial maintenance therapy for ovarian cancer. However, the mechanism leading to PARPi resistance remains unelucidated. Our study aims to screen novel targets to better predict and reverse resistance to PARPi and explore the potential mechanism. Here, we conducted a comparative analysis of differentially expressed genes between platinum-sensitive and platinum-resistant groups within the TCGA ovarian cancer cohort. The analysis indicated that lncRNA PART1 was significantly highly expressed in platinum-sensitive patients compared to platinum-resistant individuals in TCGA-OV cohort and further validated in the GEO dataset and Qilu hospital cohort. Moreover, the upregulation of PART1 was positively correlated with a favorable prognosis in ovarian cancer. Furthermore, in vitro and in vivo experiments showed that inhibition of PART1 conferred resistance to both cisplatin and PARP inhibitor and promoted cellular senescence. Senescent cells are more resistant to chemotherapeutics. RNA antisense purification and RNA immunoprecipitation assays revealed an interaction between PART1 and PHB2, a crucial mitophagy receptor. Knockdown of PART1 could promote the degradation of PHB2, impairing mitophagy and leading to cellular senescence. Rescue assays indicated that overexpression of PHB2 remarkably diminished the resistance to PARPi and cellular senescence caused by PART1 knockdown. PDX models were utilized to further confirm the findings. Altogether, our study demonstrated that lncRNA PART1 has the potential to serve as a novel promising target to reverse resistance to PARPi and improve prognosis in ovarian cancer.</p></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"602 ","pages":"Article 217192"},"PeriodicalIF":9.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304383524005871/pdfft?md5=6828b4509d3a79f06c8a94ee07c8cb92&pid=1-s2.0-S0304383524005871-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055046","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}

引用次数: 0

Enhanced desmosome assembly driven by acquired high-level desmoglein-2 promotes phenotypic plasticity and endocrine resistance in ER+ breast cancer 获得性高水平脱模谷蛋白-2驱动的脱模小体组装增强了ER+乳腺癌的表型可塑性和内分泌抗性。

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-21 DOI: 10.1016/j.canlet.2024.217179

Bohan Liu , Yuting Liu , Shuang Yang , Jingwen Ye , Jiajie Hu , Si Chen , Shiyi Wu , Qinqing Liu , Fen Tang , Yiwen Liu , Yiqing He , Yan Du , Guoliang Zhang , Qian Guo , Cuixia Yang

{"title":"Enhanced desmosome assembly driven by acquired high-level desmoglein-2 promotes phenotypic plasticity and endocrine resistance in ER+ breast cancer","authors":"Bohan Liu , Yuting Liu , Shuang Yang , Jingwen Ye , Jiajie Hu , Si Chen , Shiyi Wu , Qinqing Liu , Fen Tang , Yiwen Liu , Yiqing He , Yan Du , Guoliang Zhang , Qian Guo , Cuixia Yang","doi":"10.1016/j.canlet.2024.217179","DOIUrl":"10.1016/j.canlet.2024.217179","url":null,"abstract":"<div><p>Acquired resistance to endocrine treatments remains a major clinical challenge. In this study, we found that desmoglein-2 (DSG2) plays a major role in acquired endocrine resistance and cellular plasticity in ER<sup>+</sup> breast cancer (BC). By analysing the well-established fulvestrant-resistant ER<sup>+</sup> BC model using single-cell RNA-seq, we revealed that ER inhibition leads to a specific increase in DSG2 in cancer cell populations, which in turn enhances desmosome formation in vitro and in vivo and cell phenotypic plasticity that promotes resistance to treatment. DSG2 depletion reduced tumorigenesis and metastasis in fulvestrant-resistant xenograft models and promoted fulvestrant efficiency. Mechanistically, DSG2 forms a desmosome complex with JUP and Vimentin and triggers Wnt/PCP signalling. We showed that elevated DSG2 levels, along with reduced ER levels and an activated Wnt/PCP pathway, predicted poor survival, suggesting that a DSG2<sup>high</sup> signature could be exploited for therapeutic interventions. Our analysis highlighted the critical role of DSG2-mediated desmosomal junctions following antiestrogen treatment.</p></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"600 ","pages":"Article 217179"},"PeriodicalIF":9.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999468","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}

引用次数: 0

Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer 通过抑制 LSD1 恢复 TFPI2 可抑制肿瘤进展并增强乳腺癌的抗肿瘤免疫力

IF 9.1 1区医学

Cancer letters Pub Date : 2024-08-21 DOI: 10.1016/j.canlet.2024.217182

Tiezheng Gu , Shauna N. Vasilatos , Jun Yin , Ye Qin , Lin Zhang , Nancy E. Davidson , Yi Huang

{"title":"Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer","authors":"Tiezheng Gu , Shauna N. Vasilatos , Jun Yin , Ye Qin , Lin Zhang , Nancy E. Davidson , Yi Huang","doi":"10.1016/j.canlet.2024.217182","DOIUrl":"10.1016/j.canlet.2024.217182","url":null,"abstract":"<div><p>Histone lysine-specific demethylase 1 (<em>LSD1</em>) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with <em>Brca1</em>-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated <em>Brca1</em> loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting <em>Brca1</em>-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (<em>TFPI2</em>), is functionally associated with LSD1-mediated TNBC progression. Mouse <em>Brca1</em>-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (<em>MMPs</em>) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8<sup>+</sup> T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.</p></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"600 ","pages":"Article 217182"},"PeriodicalIF":9.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999469","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}

引用次数: 0