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UGT8 mediated sulfatide synthesis modulates BAX localization and dictates apoptosis sensitivity of colorectal cancer UGT8 介导的硫肽合成可调节 BAX 定位并决定结直肠癌对凋亡的敏感性
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-23 DOI: 10.1038/s41418-024-01418-y
Le Zhang, Prashanthi Ramesh, Lidia Atencia Taboada, Rebecca Roessler, Dick W. Zijlmans, Michiel Vermeulen, Daisy I. Picavet-Havik, Nicole N. van der Wel, Frédéric M. Vaz, Jan Paul Medema

Elevated de novo lipid synthesis is a remarkable adaptation of cancer cells that can be exploited for therapy. However, the role of altered lipid metabolism in the regulation of apoptosis is still poorly understood. Using thermal proteome profiling, we identified Manidipine-2HCl, targeting UGT8, a key enzyme in the synthesis of sulfatides. In agreement, lipidomic analysis indicated that sulfatides are strongly reduced in colorectal cancer cells upon treatment with Manidipine-2HCl. Intriguingly, this reduction led to severe mitochondrial swelling and a strong synergism with BH3 mimetics targeting BCL-XL, leading to the activation of mitochondria-dependent apoptosis. Mechanistically, Manidipine-2HCl enhanced mitochondrial BAX localization in a sulfatide-dependent fashion, facilitating its activation by BH3 mimetics. In conclusion, our data indicates that UGT8 mediated synthesis of sulfatides controls mitochondrial homeostasis and BAX localization, dictating apoptosis sensitivity of colorectal cancer cells.

新脂质合成增加是癌细胞的一种显著适应性,可用于治疗。然而,人们对脂质代谢改变在细胞凋亡调控中的作用仍然知之甚少。通过热蛋白质组分析,我们发现了马尼地平-2HCl,其靶点是合成硫化物的关键酶 UGT8。与此相一致,脂质体分析表明,在使用马尼地平-2HCl 处理结直肠癌细胞时,硫化物会强烈减少。耐人寻味的是,这种减少导致线粒体严重肿胀,并与靶向 BCL-XL 的 BH3 拟效物产生强烈的协同作用,从而激活线粒体依赖性凋亡。从机理上讲,马尼地平-2HCl 以硫化物依赖的方式增强了线粒体 BAX 的定位,促进了 BH3 拟似物对其的激活。总之,我们的数据表明,UGT8 介导的硫化物合成控制着线粒体的稳态和 BAX 的定位,从而决定了结直肠癌细胞对凋亡的敏感性。
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引用次数: 0
A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment 新型缺氧诱导lncRNA SZT2-AS1在缺氧微环境下通过介导HIF异源二聚体和组蛋白三甲基化促进HCC进展
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-22 DOI: 10.1038/s41418-024-01419-x
Runkun Liu, Yixian Guo, Liang Wang, Guozhi Yin, Hang Tuo, Yifeng Zhu, Wei Yang, Qingguang Liu, Yufeng Wang

Hypoxic microenvironment plays a critical role in solid tumor growth, metastasis and angiogenesis. Hypoxia-inducible factors (HIFs), which are canonical transcription factors in response to hypoxia, are stabilized under hypoxia and coordinate the process of hypoxia-induced gene expression, leading to cancer progression. Increasing evidence has uncovered that long noncoding RNAs (lncRNAs), which are closely associated with cancer, play crucial roles in hypoxia-mediated HCC progression, while the mechanisms are largely unknown. Here, we identified SZT2-AS1 as a novel lncRNA in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis both in vitro and in vivo. And SZT2-AS1 also mediated the hypoxia-induced HCC progression. Clinical data indicated that SZT2-AS1 level was substantially increased in HCC and closely associated with poor clinical outcomes, acting as an independent prognostic predictor. Mechanistically, SZT2-AS1 recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer, and it was required for the occupancy of HIF-1 to hypoxia response elements (HREs) and HIF target gene transcription. In addition, SZT2-AS1 was required for hypoxia-induced histone trimethylation (H3K4me3 and H3K36me3) at HREs. Through recruiting methyltransferase SMYD2, SZT2-AS1 promoted trimethylation of H3K4 and H3K36 in HCC cells. Taken together, our results uncovered a lncRNA-involved positive feedback mechanism under hypoxia and established the clinical value of SZT2-AS1 in prognosis and as a potential therapeutic target in HCC.

缺氧微环境在实体瘤的生长、转移和血管生成过程中起着至关重要的作用。缺氧诱导因子(HIFs)是应对缺氧的典型转录因子,在缺氧条件下稳定,并协调缺氧诱导的基因表达过程,从而导致癌症进展。越来越多的证据表明,与癌症密切相关的长非编码 RNAs(lncRNAs)在缺氧介导的 HCC 进展中起着至关重要的作用,但其机制目前尚不清楚。在这里,我们发现SZT2-AS1是HCC中的一种新型lncRNA,它以HIF-1依赖的方式被缺氧诱导,并在体外和体内促进HCC的生长、转移和血管生成。SZT2-AS1还介导了低氧诱导的HCC进展。临床数据表明,SZT2-AS1 水平在 HCC 中大幅升高,并与不良临床预后密切相关,是一个独立的预后预测因子。从机理上讲,SZT2-AS1能招募HIF-1α和HIF-1β形成HIF-1异源二聚体,并且是HIF-1占据缺氧反应元件(HREs)和HIF靶基因转录所必需的。此外,缺氧诱导的组蛋白三甲基化(H3K4me3 和 H3K36me3)也需要 SZT2-AS1 在 HREs 上进行。通过招募甲基转移酶 SMYD2,SZT2-AS1 促进了 HCC 细胞中 H3K4 和 H3K36 的三甲基化。综上所述,我们的研究结果揭示了缺氧条件下lncRNA参与的正反馈机制,并确定了SZT2-AS1在HCC预后中的临床价值以及作为潜在治疗靶点的可能性。
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引用次数: 0
Polyol pathway-generated fructose is indispensable for growth and survival of non-small cell lung cancer 多元醇途径产生的果糖对非小细胞肺癌的生长和存活不可或缺
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-20 DOI: 10.1038/s41418-024-01415-1
Annemarie Schwab, Mohammad Aarif Siddiqui, Vignesh Ramesh, Paradesi Naidu Gollavilli, Adriana Martinez Turtos, Sarah Søgaard Møller, Luisa Pinna, Jesper F. Havelund, Anne Mette A. Rømer, Pelin Gülizar Ersan, Beatrice Parma, Sabine Marschall, Katja Dettmer, Mohammed Alhusayan, Pietro Bertoglio, Giulia Querzoli, Dirk Mielenz, Ozgur Sahin, Nils J. Færgeman, Irfan A. Asangani, Paolo Ceppi

Despite recent treatment advances, non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide, and therefore it necessitates the exploration of new therapy options. One commonly shared feature of malignant cells is their ability to hijack metabolic pathways to confer survival or proliferation. In this study, we highlight the importance of the polyol pathway (PP) in NSCLC metabolism. This pathway is solely responsible for metabolizing glucose to fructose based on the enzymatic activity of aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD). Via genetic and pharmacological manipulations, we reveal that PP activity is indispensable for NSCLC growth and survival in vitro and in murine xenograft models. Mechanistically, PP deficiency provokes multifactorial deficits, ranging from energetic breakdown and DNA damage, that ultimately trigger the induction of apoptosis. At the molecular level, this process is driven by pro-apoptotic JNK signaling and concomitant upregulation of the transcription factors c-Jun and ATF3. Moreover, we show that fructose, the PP end-product, as well as other non-glycolytic hexoses confer survival to cancer cells and resistance against chemotherapy via sustained NF-κB activity as well as an oxidative switch in metabolism. Given the detrimental consequence of PP gene targeting on growth and survival, we propose PP pathway interference as a viable therapeutic approach against NSCLC.

尽管最近的治疗取得了进展,但非小细胞肺癌(NSCLC)仍然是全球癌症相关死亡的主要原因之一,因此有必要探索新的治疗方案。恶性细胞的一个共同特征是它们能够劫持代谢途径以获得生存或增殖。在本研究中,我们强调了多元醇途径(PP)在 NSCLC 代谢中的重要性。基于醛糖还原酶(AKR1B1)和山梨醇脱氢酶(SORD)的酶活性,该途径只负责将葡萄糖代谢为果糖。通过基因和药理学操作,我们发现 PP 活性对于 NSCLC 在体外和小鼠异种移植模型中的生长和存活是不可或缺的。从机理上讲,PP 缺乏会导致能量分解和 DNA 损伤等多因素缺陷,最终引发细胞凋亡。在分子水平上,这一过程是由促凋亡的 JNK 信号以及转录因子 c-Jun 和 ATF3 的同步上调所驱动的。此外,我们还发现 PP 的最终产物果糖以及其他非糖化己糖通过持续的 NF-κB 活性和新陈代谢中的氧化转换赋予癌细胞生存能力和抗化疗能力。鉴于 PP 基因靶向对生长和存活的不利影响,我们建议将 PP 通路干扰作为治疗 NSCLC 的一种可行方法。
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引用次数: 0
KBTBD2 controls bone development by regulating IGF-1 signaling during osteoblast differentiation KBTBD2 在成骨细胞分化过程中通过调节 IGF-1 信号控制骨骼发育
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1038/s41418-024-01416-0
Yu Xun, Yiao Jiang, Aysha Khalid, Zeru Tian, Jonathan Rios, Zhao Zhang

Kelch repeat and BTB (POZ) domain-containing 2 (KBTBD2) is known for its pivotal role in metabolic regulation, particularly in adipocytes. However, its significance in skeletal development has remained elusive. Here, we uncover a previously unrecognized function of KBTBD2 in bone formation. Conditional knockout of Kbtbd2 in embryonic osteochondroprogenitor cells or osteoblasts results in impaired osteogenic differentiation, leading to reduced skeletal growth and mineralization. Mechanistically, the loss of KBTBD2 during osteogenesis leads to the accumulation of p85α, a regulatory subunit encoded by phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1), which exerts a potent inhibitory effect on insulin-like growth factor 1 (IGF-1)-induced activation of AKT. Moreover, our study extends the understanding of KBTBD2’s relevance beyond bone biology to the context of SHORT syndrome, a rare genetic disorder marked by short stature and various physical abnormalities. We demonstrate that p85α harboring the p.(Arg649Trp) mutation, most frequently found in SHORT syndrome patients, exhibits reduced binding to KBTBD2, leading to impaired IGF-1-mediated activation of AKT. These findings reveal that KBTBD2 is essential in bone formation via regulating the IGF-1 signaling pathway and suggest loss of KBTBD2-mediated regulation of p85α as a potential mechanism for SHORT syndrome.

众所周知,含 Kelch 重复和 BTB(POZ)结构域的 2(KBTBD2)在新陈代谢调节中起着关键作用,尤其是在脂肪细胞中。然而,它在骨骼发育过程中的意义却一直难以捉摸。在这里,我们发现了 KBTBD2 在骨骼形成过程中的一种以前未被发现的功能。在胚胎成骨细胞或成骨细胞中条件敲除 Kbtbd2 会导致成骨分化受损,从而导致骨骼生长和矿化减少。从机理上讲,成骨过程中 KBTBD2 的缺失会导致 p85α 的积累,p85α 是磷酸肌醇-3-激酶调节亚基 1(Pik3r1)编码的一种调节亚基,它对胰岛素样生长因子 1(IGF-1)诱导的 AKT 激活有强效抑制作用。此外,我们的研究还将 KBTBD2 的相关性从骨骼生物学扩展到了 SHORT 综合征,这是一种以身材矮小和各种身体异常为特征的罕见遗传性疾病。我们证明,在 SHORT 综合征患者中最常发现的 p85α 存在 p.(Arg649Trp) 突变,它与 KBTBD2 的结合力降低,导致 IGF-1 介导的 AKT 激活功能受损。这些发现揭示了 KBTBD2 通过调节 IGF-1 信号通路在骨骼形成过程中的重要作用,并提示 KBTBD2 介导的 p85α 调节功能缺失是 SHORT 综合征的一种潜在机制。
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引用次数: 0
ACBP/DBI neutralization for the experimental treatment of fatty liver disease. ACBP/DBI 中和用于脂肪肝的实验治疗。
IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-16 DOI: 10.1038/s41418-024-01410-6
Omar Motiño, Flavia Lambertucci, Adrien Joseph, Sylvère Durand, Gerasimos Anagnostopoulos, Sijing Li, Vincent Carbonnier, Uxía Nogueira-Recalde, Léa Montégut, Hui Chen, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Chiara Maiuri, Federico Pietrocola, Dominique Valla, Cédric Laouénan, Jean-François Gautier, Laurent Castera, Isabelle Martins, Guido Kroemer

Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl4, and (iv) a combination of CCl4 injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.

酰基-CoA 结合蛋白(ACBP)又称地西泮结合抑制剂(DBI),是自噬的细胞外检查点。我们在此报告,与未受影响的对照组相比,经组织学证实的代谢相关性脂肪性肝炎(MASH)或肝纤维化患者表现出循环 ACBP/DBI 蛋白水平升高。血浆 ACBP/DBI 与患者的非酒精性脂肪肝和 FIB4 评分密切相关,而且这些相关性与年龄和体重指数无关。我们研究了中和小鼠 ACBP/DBI 的单克隆抗体(mAb)在几种小鼠模型中防治活动性肝病的能力,这些小鼠模型由四种不同的方案诱发脂肪性肝炎,即(i)蛋氨酸/胆碱缺乏饮食,(ii)单独西式饮食(WD),(iii)西式饮食与肝毒性药物 CCl4 结合,以及(iv)注射 CCl4 和口服乙醇挑战相结合。在这四种模型中,注射抗 ACBP/DBI mAb 可减轻肝损伤的组织学、酶学、代谢组学和转录组学迹象,从而阻止或减少非酒精性和酒精性肝病的进展。在临床前水平上,脂肪变性、炎症、气球扩张和纤维化对 ACBP/DBI 抑制有反应。总之,这些发现支持 ACBP/DBI 在 MASH 和肝纤维化中的因果作用,以及针对 ACBP/DBI 进行治疗的可能性。
{"title":"ACBP/DBI neutralization for the experimental treatment of fatty liver disease.","authors":"Omar Motiño, Flavia Lambertucci, Adrien Joseph, Sylvère Durand, Gerasimos Anagnostopoulos, Sijing Li, Vincent Carbonnier, Uxía Nogueira-Recalde, Léa Montégut, Hui Chen, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Chiara Maiuri, Federico Pietrocola, Dominique Valla, Cédric Laouénan, Jean-François Gautier, Laurent Castera, Isabelle Martins, Guido Kroemer","doi":"10.1038/s41418-024-01410-6","DOIUrl":"https://doi.org/10.1038/s41418-024-01410-6","url":null,"abstract":"<p><p>Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl<sub>4</sub>, and (iv) a combination of CCl<sub>4</sub> injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643750","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
AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis AKAP1/PKA 介导的线粒体相关内质网膜上的 GRP75 磷酸化可保护癌细胞免受铁中毒的侵害
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-13 DOI: 10.1038/s41418-024-01414-2
Hao Liu, Shanliang Zheng, Guixue Hou, Junren Dai, Yanan Zhao, Fan Yang, Zhiyuan Xiang, Wenxin Zhang, Xingwen Wang, Yafan Gong, Li Li, Ning Zhang, Ying Hu

Emerging evidence suggests that signaling pathways can be spatially regulated to ensure rapid and efficient responses to dynamically changing local cues. Ferroptosis is a recently defined form of lipid peroxidation-driven cell death. Although the molecular mechanisms underlying ferroptosis are emerging, spatial aspects of its signaling remain largely unexplored. By analyzing a public database, we found that a mitochondrial chaperone protein, glucose-regulated protein 75 (GRP75), may have a previously undefined role in regulating ferroptosis. This was subsequently validated. Interestingly, under ferroptotic conditions, GRP75 translocated from mitochondria to mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and the cytosol. Further mechanistic studies revealed a highly spatial regulation of GRP75-mediated antiferroptotic signaling. Under ferroptotic conditions, lipid peroxidation predominantly accumulated at the ER, which activated protein kinase A (PKA) in a cAMP-dependent manner. In particular, a signaling microdomain, the outer mitochondrial membrane protein A-kinase anchor protein 1 (AKAP1)-anchored PKA, phosphorylated GRP75 at S148 in MAMs. This caused GRP75 to be sequestered outside the mitochondria, where it competed with Nrf2 for Keap1 binding through a conserved high-affinity RGD-binding motif, ETGE. Nrf2 was then stabilized and activated, leading to the transcriptional activation of a panel of antiferroptotic genes. Blockade of the PKA/GRP75 axis dramatically increased the responses of cancer cells to ferroptosis both in vivo and in vitro. Our identification a localized signaling cascade involved in protecting cancer cells from ferroptosis broadens our understanding of cellular defense mechanisms against ferroptosis and also provides a new target axis (AKAP1/PKA/GRP75) to improve the responses of cancer cells to ferroptosis.

新的证据表明,信号通路可以在空间上进行调节,以确保对动态变化的局部线索做出快速有效的反应。铁变性是最近定义的一种脂质过氧化驱动的细胞死亡形式。尽管铁凋亡的分子机制正在形成,但其信号传导的空间方面在很大程度上仍未得到探索。通过分析公共数据库,我们发现线粒体伴侣蛋白--葡萄糖调节蛋白 75(GRP75)--可能在调控铁中毒中发挥着之前未定义的作用。这一发现随后得到了验证。有趣的是,在铁凋亡条件下,GRP75 从线粒体转位到线粒体相关内质网(ER)膜(MAMs)和细胞质。进一步的机理研究揭示了 GRP75 介导的抗铁锈色素沉着信号的高度空间调控。在铁凋亡条件下,脂质过氧化主要积聚在ER,从而以cAMP依赖性方式激活蛋白激酶A(PKA)。特别是,线粒体外膜蛋白A-激酶锚定蛋白1(AKAP1)锚定的PKA信号微域在MAMs中的S148处磷酸化了GRP75。这导致 GRP75 被封闭在线粒体外,在线粒体外,它通过一个保守的高亲和性 RGD 结合基序 ETGE 与 Nrf2 竞争 Keap1 的结合。然后,Nrf2 被稳定和激活,导致一系列抗铁锈色素基因的转录激活。阻断 PKA/GRP75 轴可显著提高癌细胞在体内和体外对铁变态反应的反应。我们发现了一个参与保护癌细胞免受铁变态反应的局部信号级联,这拓宽了我们对细胞防御铁变态反应机制的理解,同时也提供了一个新的靶轴(AKAP1/PKA/GRP75)来改善癌细胞对铁变态反应的反应。
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引用次数: 0
Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system 转录激酶 CDK12 和 CDK13 在中枢神经系统中的生理和病理作用
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-12 DOI: 10.1038/s41418-024-01413-3
Consuelo Pitolli, Alberto Marini, Claudio Sette, Vittoria Pagliarini

The cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) govern several steps of gene expression, including transcription, RNA processing and translation. The main target of CDK12/13 is the serine 2 residue of the carboxy-terminal domain of RNA polymerase II (RNAPII), thus influencing the directionality, elongation rate and processivity of the enzyme. The CDK12/13-dependent regulation of RNAPII activity influences the expression of selected target genes with important functional roles in the proliferation and viability of all eukaryotic cells. Neuronal cells are particularly affected by the loss of CDK12/13, as result of the high dependency of neuronal genes on RNAPII processivity for their expression. Deregulation of CDK12/13 activity strongly affects brain physiology by influencing the stemness potential and differentiation properties of neuronal precursor cells. Moreover, mounting evidence also suggest the involvement of CDK12/13 in brain tumours. Herein, we discuss the functional role(s) of CDK12 and CDK13 in gene expression regulation and highlight similarities and differences between these highly homologous kinases, with particular attention to their impact on brain physiology and pathology. Lastly, we provide an overview of CDK12/13 inhibitors and of their efficacy in brain tumours and other neoplastic diseases.

细胞周期蛋白依赖性激酶 12(CDK12)和 13(CDK13)控制着基因表达的几个步骤,包括转录、RNA 处理和翻译。CDK12/13 的主要靶标是 RNA 聚合酶 II(RNAPII)羧基末端结构域的丝氨酸 2 残基,从而影响该酶的方向性、伸长率和过程活性。CDK12/13 依赖于对 RNAPII 活性的调控,它影响着对所有真核细胞的增殖和活力具有重要功能作用的特定靶基因的表达。由于神经元基因的表达高度依赖于 RNAPII 的活性,CDK12/13 的缺失对神经元细胞的影响尤为明显。CDK12/13 活性的失调会影响神经元前体细胞的干潜能和分化特性,从而对大脑生理产生强烈影响。此外,越来越多的证据也表明 CDK12/13 与脑肿瘤有关。在此,我们将讨论 CDK12 和 CDK13 在基因表达调控中的功能作用,并强调这些高度同源激酶之间的异同,尤其关注它们对大脑生理和病理的影响。最后,我们概述了 CDK12/13 抑制剂及其对脑肿瘤和其他肿瘤性疾病的疗效。
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引用次数: 0
Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance 整合素β6/附件素A2轴触发自噬,协调肝细胞癌的放射抗性
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-12 DOI: 10.1038/s41418-024-01411-5
Ying Gao, Guangyan Wei, Hua Yu, Shuping Li, Yuhao Tang, Xin Yue, Yong Chen, Meixiao Zhan, Jian Wu

Radiotherapy (RT) is one of the main therapies for hepatocellular carcinoma (HCC), but its effectiveness has been constrained due to the resistance effect of radiation. Thus, the factors involved in radioresistance are evaluated and the underlying molecular mechanisms are also done. In this present study, we identified Integrin β6 (ITGB6) as a potential radioresistant gene through an integrative analysis of transcriptomic profiles, proteome datasets and survival using HCC cases treated with IR. We show that ITGB6 functionally contributed to radioresistance by activating autophagy through a series of in vitro and in vivo methods, such as clonogenic assays, autophagy flux (LC3B-GFP-mCherry reporter) analysis and a subcutaneous transplantation model. Mechanically, ITGB6 binds to Annexin A2 (ANXA2) and enhanced its stability by competitively antagonizing proteasome mediated ANXA2 degradation, thereby promoting autophagy and radioresistance. Notably, HCC radioresistance was significantly improved by either blocking ITGB6 or autophagy, but the combination was more effective. Importantly, ITGB6/ANXA2 axis triggered autophagic program endowed HCC cells with radioresistant activity in a radiated patient-derived xenograft (PDX) model and hydrodynamic injection in liver-specific Itgb6-knockout mice, further supported by clinical evidence. Together, our data revealed that ITGB6 is a radioresistant gene stabilizing the autophagy regulatory protein ANXA2, providing insights into the biological and potentially clinical significance of ITGB6/ANXA2 axis in radiotherapy planning of HCC.

放射治疗(RT)是治疗肝细胞癌(HCC)的主要疗法之一,但由于放射的抗药性效应,其有效性受到了限制。因此,我们对放射抗性的相关因素进行了评估,并对其潜在的分子机制进行了研究。在本研究中,我们利用接受过红外线治疗的 HCC 病例,通过对转录组图谱、蛋白质组数据集和存活率的综合分析,确定了 Integrin β6 (ITGB6) 是一种潜在的放射抗性基因。我们通过一系列体外和体内方法,如克隆形成试验、自噬通量(LC3B-GFP-mCherry报告物)分析和皮下移植模型,证明了ITGB6通过激活自噬在功能上促进了放射抗性。从机理上讲,ITGB6能与Annexin A2(ANXA2)结合,并通过竞争性拮抗蛋白酶体介导的ANXA2降解来增强其稳定性,从而促进自噬和放射抗性。值得注意的是,无论是阻断 ITGB6 还是自噬,都能显著改善 HCC 的放射抗性,但联合使用效果更好。重要的是,ITGB6/ANXA2 轴触发的自噬程序使 HCC 细胞在放射性患者异种移植(PDX)模型和肝特异性 Itgb6 基因敲除小鼠的水动力注射中具有抗放射活性,临床证据进一步证实了这一点。总之,我们的数据揭示了 ITGB6 是一种稳定自噬调控蛋白 ANXA2 的抗放射基因,为 ITGB6/ANXA2 轴在 HCC 放射治疗计划中的生物学意义和潜在临床意义提供了见解。
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引用次数: 0
hnRNPA2B1 deacetylation by SIRT6 restrains local transcription and safeguards genome stability SIRT6 对 hnRNPA2B1 的去乙酰化作用可抑制局部转录并保护基因组稳定性
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-07 DOI: 10.1038/s41418-024-01412-4
Feng Chen, Wenchao Xu, Ming Tang, Yuan Tian, Yuxin Shu, Xingkai He, Linmin Zhou, Qi Liu, Qian Zhu, Xiaopeng Lu, Jun Zhang, Wei-Guo Zhu

Repair of double strand breaks (DSBs) by RNA-binding proteins (RBPs) is vital for ensuring genome integrity. DSB repair is accompanied by local transcriptional repression in the vicinity of transcriptionally active genes, but the mechanism by which RBPs regulate transcriptional regulation is unclear. Here, we demonstrated that RBP hnRNPA2B1 functions as a RNA polymerase-associated factor that stabilizes the transcription complex under physiological conditions. Following a DSB, hnRNPA2B1 is released from damaged chromatin, reducing the efficiency of RNAPII complex assembly, leading to local transcriptional repression. Mechanistically, SIRT6 deacetylates hnRNPA2B1 at K113/173 residues, enforcing its rapid detachment from DSBs. This process disrupts the integrity of the RNAPII complex on active chromatin, which is a pre-requisite for transient but complete repression of local transcription. Functionally, the overexpression of an acetylation mimic stabilizes the transcription complex and facilitates the functioning of the transcription machinery. hnRNPA2B1 acetylation status was negatively correlated with SIRT6 expression, and acetylation mimic enhanced radio-sensitivity in vivo. Our findings demonstrate that hnRNPA2B1 is crucial for transcriptional repression. We have uncovered the missing link between DSB repair and transcriptional regulation in genome stability maintenance, highlighting the potential of hnRNPA2B1 as a therapeutic target.

RNA 结合蛋白(RBPs)对双链断裂(DSB)的修复对确保基因组完整性至关重要。DSB修复伴随着转录活跃基因附近的局部转录抑制,但RBP调节转录的机制尚不清楚。在这里,我们证明了 RBP hnRNPA2B1 在生理条件下作为 RNA 聚合酶相关因子稳定转录复合物的功能。DSB发生后,hnRNPA2B1从受损染色质中释放出来,降低了RNAPII复合物的组装效率,导致局部转录抑制。从机理上讲,SIRT6 会在 K113/173 残基上对 hnRNPA2B1 进行去乙酰化,从而使其快速脱离 DSB。这一过程破坏了活性染色质上 RNAPII 复合物的完整性,而这是瞬时但完全抑制局部转录的先决条件。hnRNPA2B1 的乙酰化状态与 SIRT6 的表达呈负相关,乙酰化模拟物增强了体内的放射敏感性。我们的研究结果表明,hnRNPA2B1 对转录抑制至关重要。我们发现了基因组稳定性维持过程中DSB修复和转录调控之间缺失的环节,凸显了hnRNPA2B1作为治疗靶点的潜力。
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引用次数: 0
Correction: STAT3 dictates β-cell apoptosis by modulating PTEN in streptozocin-induced hyperglycemia 更正:STAT3 在链脲佐菌素诱导的高血糖中通过调节 PTEN 决定β细胞凋亡
IF 12.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-07 DOI: 10.1038/s41418-024-01405-3
Qinjie Weng, Mengting Zhao, Jiahuan Zheng, Lijun Yang, Zijie Xu, Zhikang Zhang, Jincheng Wang, Jiajia Wang, Bo Yang, Q. Richard Lu, Meidan Ying, Qiaojun He
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引用次数: 0
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Cell Death and Differentiation
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