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The kinase PLK1 promotes Hedgehog signaling–dependent resistance to the antiandrogen enzalutamide in metastatic prostate cancer

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-18 DOI: 10.1126/scisignal.adi5174

Qiongsi Zhang, Jia Peng, Yanquan Zhang, Jinghui Liu, Daheng He, Yue Zhao, Xinyi Wang, Chaohao Li, Yifan Kong, Ruixin Wang, Fengyi Mao, Chi Wang, Qing Wang, Min Zhang, Jianlin Wang, Hsin-Sheng Yang, Xiaoqi Liu

{"title":"The kinase PLK1 promotes Hedgehog signaling–dependent resistance to the antiandrogen enzalutamide in metastatic prostate cancer","authors":"Qiongsi Zhang, Jia Peng, Yanquan Zhang, Jinghui Liu, Daheng He, Yue Zhao, Xinyi Wang, Chaohao Li, Yifan Kong, Ruixin Wang, Fengyi Mao, Chi Wang, Qing Wang, Min Zhang, Jianlin Wang, Hsin-Sheng Yang, Xiaoqi Liu","doi":"10.1126/scisignal.adi5174","DOIUrl":"10.1126/scisignal.adi5174","url":null,"abstract":"<div >Enzalutamide, a second-generation androgen receptor inhibitor (also known as an antiandrogen), is used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Tumors often acquire resistance to enzalutamide. Tumor progression and enzalutamide resistance are associated with decreased abundance of the tumor suppressor PDCD4. In normal dividing cells, PDCD4 abundance is low when that of the kinase PLK1 is high. In this study, we found that PLK1 acted on PDCD4 to promote enzalutamide resistance in CRPC cells in culture and in mice via a mechanism that revealed an effective combination therapy. PLK1 phosphorylated PDCD4 at Ser<sup>239</sup>, leading to its degradation and consequently inducing the transcriptional activation of Hedgehog (Hh) signaling by c-MYC. Hh signaling supports tumor cell proliferation and stemness by inducing the enzyme UDP-glucuronosyltransferase 2B15 (UGT2B15), which promotes the metabolic clearance of drugs and steroid hormones. Thus, this pathway may circumvent androgen receptor dependence, thereby reducing cellular sensitivity to enzalutamide. Knocking down UGT2B15 enhanced enzalutamide-induced cell apoptosis and growth arrest in a PDCD4-dependent manner. Combining enzalutamide with the clinically approved Hh pathway inhibitor vismodegib inhibited cell growth and promoted apoptosis in enzalutamide-resistant cell cultures and xenografts in vivo. Our findings reveal a mechanism of PLK1-mediated enzalutamide resistance and suggest a potential therapeutic strategy to overcome this resistance in prostate cancer.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 878","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adi5174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-11

Wei Wang, Jichao Liang, Yinliang Zhang, Junjun Wang, Xiaolei Miao, Yongsheng Chang, Yong Chen

{"title":"Myeloid sirtuin 6 deficiency causes obesity in mice by inducing norepinephrine degradation to limit thermogenic tissue function","authors":"Wei Wang, Jichao Liang, Yinliang Zhang, Junjun Wang, Xiaolei Miao, Yongsheng Chang, Yong Chen","doi":"","DOIUrl":"","url":null,"abstract":"<div >Brown and beige adipocytes dissipate energy to generate heat through uncoupled respiration, and the hormone norepinephrine plays an important role in stimulating brown fat thermogenesis and beige adipocyte development in white adipose depots. Increasing energy expenditure by promoting the function and development of brown and beige fat is a potential approach to treat obesity and diabetes. Here, we investigated the effects of macrophage sirtuin 6 (SIRT6<i></i>) on the regulation of the norepinephrine content of brown adipose tissue (BAT) and on obesity in mice. Myeloid SIRT6<i></i> deficiency impaired the thermogenic function of BAT, thereby decreasing core body temperatures because of reduced norepinephrine concentrations in BAT and subsequently leading to cold sensitivity. In addition, the oxygen consumption rate was reduced, resulting in severe insulin resistance and obesity. Furthermore, macrophage SIRT6<i></i> deficiency inhibited BAT thermogenesis after cold exposure or norepinephrine treatment and cold exposure–induced increases in markers of lipid metabolism and thermogenesis in white adipose tissue. Myeloid-specific SIRT6<i></i> deficiency promoted H3K9 acetylation in the promoter regions and the expression of genes encoding the norepinephrine-degrading enzyme MAOA and the norepinephrine transporter SLC6A2 in macrophages in BAT, leading to norepinephrine degradation and obesity. Our findings indicate that SIRT6 in macrophages is essential for maintaining norepinephrine concentrations in BAT in mice.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 877","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NEMO is essential for directing the kinases IKKα and ATM to the sites of DNA damage NEMO 对引导激酶 IKKα 和 ATM 到达 DNA 损伤部位至关重要

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-11

Josune Alonso-Marañón, Laura Solé, Daniel Álvarez-Villanueva, María Maqueda, Teresa Lobo-Jarne, Ángela Montoto, Jose Yélamos, Eva Borràs, Leire Uraga, Christopher Hooper, Eduard Sabidó, Shigeki Miyamoto, Anna Bigas, Lluís Espinosa

{"title":"NEMO is essential for directing the kinases IKKα and ATM to the sites of DNA damage","authors":"Josune Alonso-Marañón, Laura Solé, Daniel Álvarez-Villanueva, María Maqueda, Teresa Lobo-Jarne, Ángela Montoto, Jose Yélamos, Eva Borràs, Leire Uraga, Christopher Hooper, Eduard Sabidó, Shigeki Miyamoto, Anna Bigas, Lluís Espinosa","doi":"","DOIUrl":"","url":null,"abstract":"<div >The DNA damage repair kinase ATM is phosphorylated by the NF-κB pathway kinase IKKα, resulting in enhanced DNA damage repair through the nonhomologous end-joining pathway. Thus, inhibition of IKKα enhances the efficacy of cancer therapy based on inducing DNA damage. Here, we found a role for the IKK regulatory subunit NEMO in DNA damage repair mediated by ATM and IKKα. Exposure to damaging agents induced the interaction of NEMO with a preformed ATM-IKKα complex, which was required to target active ATM and IKKα to chromatin for efficient DNA damage repair but not for activating ATM. Recognition of damaged DNA by the IKKα-NEMO-ATM complex was facilitated by the interaction between NEMO and histones and depended on the ADP ribosylation of histones by the enzyme PARP1. NEMO-deficient cells showed increased activity of the kinase ATR, and inhibition of ATR potentiated the effect of chemotherapy in cells lacking NEMO or IKKα. Bioinformatic analysis of colorectal cancer datasets demonstrated that the expression of genes encoding IKKα, NEMO, and ATM correlated with poor patient prognosis, suggesting that the mechanism linking these three elements may be clinically relevant.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 877","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic pressure from sensory neurons

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-11

Wei Wong

引用次数: 0

The NEMO/ATM/IKKα complex: A key player in colorectal cancer progression and treatment NEMO/ATM/IKKα 复合物：结直肠癌进展和治疗中的关键角色

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-11

Neil D. Perkins

引用次数: 0

Making sense of gastric cancer

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-04

Amy E. Baek

引用次数: 0

The acetyltransferase GCN5 contributes to neuroinflammation in mice by acetylating and activating the NF-κB subunit p65 in microglia

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-03-04

Duk-Yeon Cho, Jun-Hyuk Han, In-Su Kim, Ji-Hong Lim, Hyun Myung Ko, Byungwook Kim, Dong-Kug Choi

{"title":"The acetyltransferase GCN5 contributes to neuroinflammation in mice by acetylating and activating the NF-κB subunit p65 in microglia","authors":"Duk-Yeon Cho, Jun-Hyuk Han, In-Su Kim, Ji-Hong Lim, Hyun Myung Ko, Byungwook Kim, Dong-Kug Choi","doi":"","DOIUrl":"","url":null,"abstract":"<div >Neuroinflammation promotes the progression of various neurological and neurodegenerative diseases. Disrupted homeostasis of protein acetylation is implicated in neurodegeneration, and the lysine acetyltransferase GCN5 (also known as KAT2A) is implicated in peripheral inflammation. Here, we investigated whether GCN5 plays a role in neuroinflammation in the brain. Systemic administration of the bacterial molecule LPS in mice to induce peripheral inflammation increased the abundance of GCN5 in various organs, including in the brain and specifically in microglia. In response to LPS, GCN5 mediated the induction of the proinflammatory cytokines TNF-α and IL-6 and the inflammatory mediators COX-2 and iNOS in microglia. Further investigation in cultured microglial cells revealed that GCN5 was activated downstream of the innate immune receptor TLR4 to acetylate Lys<sup>310</sup> in the NF-κB subunit p65, thereby enabling the nuclear translocation and transcriptional activity of NF-κB and the resulting inflammatory response. Thus, targeting GCN5 might be explored further as a strategy to reduce neuroinflammation in the treatment of associated diseases.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 876","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adp8973","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A sequencing-based screening method identifies regulators of EGFR signaling from nonviable mutants in Caenorhabditis elegans

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-02-25

Hillel T. Schwartz, Paul W. Sternberg

{"title":"A sequencing-based screening method identifies regulators of EGFR signaling from nonviable mutants in Caenorhabditis elegans","authors":"Hillel T. Schwartz, Paul W. Sternberg","doi":"","DOIUrl":"","url":null,"abstract":"<div >Suppressor screens can identify genetic modifiers of biochemical pathways but generally require that the suppressed mutant be viable and fertile. We developed a screening method that obviated this requirement and enabled the identification of mutations that partially suppressed the early developmental arrest and lethality caused by loss of the epidermal growth factor (EGF) receptor ortholog LET-23 in <i>Caenorhabditis elegans</i>. We chemically mutagenized animals carrying the loss-of-function allele <i>let-23</i>(<i>sy15</i>), recovered <i>let-23</i>(<i>sy15</i>) homozygotes that escaped early developmental arrest but were nevertheless inviable, and sequenced their genomes. Testing of candidate causal mutations identified 11 genes that, when mutated, mitigated the early lethality caused by loss of EGF signaling. These included genes encoding homologs of the small guanosine triphosphatase (GTPase) Ras (<i>let-60</i>), which is a downstream effector of LET-23, and of regulators of the small GTPase Rho, including the homolog of the phosphotyrosine-binding protein TENSIN (<i>tns-1</i>). We also recovered suppressing mutations in genes encoding nuclear proteins that protect against DNA damage, including the homolog of MutS homolog 4 (<i>him-14</i>). Genetic experiments were consistent with the repression of Rho activity or the activation of the DNA damage response compensating for the loss of EGF signaling. This sequencing-based, whole-animal screening method may be adapted to other organisms to enable the identification of mutations for which the phenotype does not allow the recovery of viable animals.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 875","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glutamatergic argonaute2 promotes the formation of the neurovascular unit in mice

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-02-25

Chandan Sona, Yu-Te Yeh, Yunxiao Li, Xiaoxuan Liu, Adhideb Ghosh, Laura C. Hinte, Min-Chi Ku, Thomas Rathjen, Thoralf Niendorf, Guoxing Yu, Shiqi Jia, Natalia L. Kononenko, Andreas Hermann, Jiankai Luo, Juntang Lin, Ferdinand von Meyenn, Xin Yan, Matthew N. Poy

{"title":"Glutamatergic argonaute2 promotes the formation of the neurovascular unit in mice","authors":"Chandan Sona, Yu-Te Yeh, Yunxiao Li, Xiaoxuan Liu, Adhideb Ghosh, Laura C. Hinte, Min-Chi Ku, Thomas Rathjen, Thoralf Niendorf, Guoxing Yu, Shiqi Jia, Natalia L. Kononenko, Andreas Hermann, Jiankai Luo, Juntang Lin, Ferdinand von Meyenn, Xin Yan, Matthew N. Poy","doi":"","DOIUrl":"","url":null,"abstract":"<div >Proper formation of the complex neurovascular unit (NVU) along with the blood-brain barrier is critical for building and sustaining a healthy, functioning central nervous system. The RNA binding protein argonaute2 (Ago2) mediates microRNA (miRNA)–mediated gene silencing, which is critical for many facets of brain development, including NVU development. Here, we found that <i>Ago2</i> in glutamatergic neurons was critical for NVU formation in the developing cortices of mice. Glutamatergic neuron–specific loss of <i>Ago2</i> diminished synaptic formation, neuronal-to-endothelial cell contacts, and morphogenesis of the brain vasculature, ultimately compromising the integrity of the blood-brain barrier. Ago2 facilitated miRNA targeting of <i>phosphatase and tensin homolog</i> (<i>Pten</i>) mRNA, which encodes a phosphatase that modulates reelin-dependent phosphatidylinositol 3-kinase (PI3K)–Akt signaling within the glutamatergic subpopulation. Conditionally deleting <i>Pten</i> in <i>Ago2</i>-deficient neurons restored Akt2 phosphorylation as well as postnatal development and survival. Several mutations in <i>AGO2</i> impair small RNA silencing and are associated with Lessel-Kreienkamp syndrome, a neurodevelopmental disorder. When expressed in a neuronal cell line, these human <i>AGO2</i> loss-of-function variants failed to suppress PTEN, resulting in attenuated PI3K-Akt signaling, further indicating that dysregulation of Ago2 function may contribute to both impaired development and neurological disorders. Together, these results identify Ago2 as central to the engagement of neurons with blood vessels in the developing brain.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 875","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dulling the sweet tooth

IF 6.7 1区生物学

Science Signaling Pub Date : 2025-02-25

Annalisa M. VanHook

引用次数: 0