NATURE CELL BIOLOGY
·
2024
·
IF 17.3
Son Sung Min,Park So Jung,Breusegem Sophia Y.,Larrieu Delphine,Rubinsztein David C.
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism and autophagy. Multiple pathways modulate mTORC1 in response to nutrients. Here we describe that nucleus–cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300 that decreases acetylation of the mTORC1 component raptor, thereby reducing mTORC1 activity and activating autophagy. This is mediated by AMP-activated protein kinase-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in protein phosphatase 2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. Interestingly, p300 cytoplasm–nucleus shuttling is altered in cells from patients with Hutchinson–Gilford progeria syndrome. p300 mislocalization by the disease-causing protein, progerin, activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in Hutchinson–Gilford progeria syndrome, causing mTORC1 hyperactivation and defective autophagy.
研究领域:
细胞生物学
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分子生物学
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医学遗传学
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DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2019
·Vol. 186
·期 5
·1-10
·
IF 5.479
Hu Yufang,Zhang Qingqing,Hu Dandan,Wang Jiao,Rao Jiajia,Xu Lihua,Guo Zhiyong,Wang Sui,Liu Xin,Tang Shiyun,Shen Qinpeng
Protein p300 is a transcriptional co-activator that participates in many physiological processes including cell cycle control, differentiation and apoptosis. It serves (a) as a protein bridge that links specific transcription factors to the fundamental transcription machinery, (b) as a scaffold to complete multiple transcription cofactors, and (c) as an enzyme for acetylating histone and non-histone proteins. An ultrasensitive electrochemiluminescence (ECL) immunosensor is described here that is based on the use of a magnetic glassy carbon electrode modified with tetrahedral DNA with hollow structure, graphene oxide (GO) and gold nanocrystals. The use of a GO monolayer allows for greater carrying capacity and warrants a wider outer Helmholtz plane. Strong and stable ECL signals were achieved due to antigen-antibody interaction by using the ECL probe Ru(phen) 3 2+ . This immunosensor has a response that covers the 0.005 to 80 nM p300 concentration range and has a 1 pM detection limit. It was exploited for the determination of p300 in HeLa cell lysate and (spiked) serum.
Schematic presentation of an ultrasensitive Faraday-cage electrochemiluminescence immunosensor toward the transcriptional co-activator p300 analysis is presented based on a graphene oxide monolayer and tetrahedral DNA-mediated signal amplification.
研究领域:
生物化学
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纳米技术
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分析化学
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生物医学工程
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PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2025
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IF 15.4
Chen Zixiang,Niu Kaifeng,Li Mengge,Deng Yuchun,Zhang Ji,Wei Di,Wang Jiaqi,Zhao Yongliang
Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.
研究领域:
肿瘤生物学
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细胞代谢
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表观遗传学
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DOI
PubMed
高影响因子
Advanced Science
·
2026
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IF 14.1
Zhengquan Zhu,Yihan Wang,Haiyun Chen,Xinye Yu,Tingyu Wang,Yajing Weng,Meihong Guo,Ying Huang,Gaojian Tao,Wangsen Cao,Yong Wang,Daojuan Wang
Persistent androgen receptor (AR) activation is an important contributor to polycystic ovary syndrome (PCOS) and is affected by transcriptional regulation via histone acetylation; however, the underlying mechanisms are partially understood. This study demonstrated that AR activation in ovarian granulosa cells (GCs) of both dehydroepiandrosterone (DHEA) and high-fat diet-induced PCOS mouse models correlated with a significant increase in the histone acetyltransferase p300 and histone acetylation. Conversely, GC-specific p300 knockout or pharmacological inhibition with C646/A-485 effectively reduced AR activation, histone 3 acetylation (H3K18ac/H3K27ac), and ovarian fibrosis in PCOS mice, highlighting p300 as a critical driver. ATAC-seq and RNA-seq identified “open” chromatin regions at the AR promoter in PCOS ovaries, corresponding with increased AR transcription and histone acetylation. p300, along with transcription factor SP1 and the acetyl-reader BRD4, bound to H3K18ac and H3K27ac of the AR promoter in PCOS-modeled ovaries and GCs, which was blocked by C646 and the SP1 inhibitor Plicamycin, respectively. Importantly, continuous AR activation by its ligand DHT largely diminished the anti-fibrotic and ovarian-protective effects of C646. These findings suggest that p300, SP1, and BRD4, form a critical transcriptional complex driving AR activation and PCOS development, and that targeting the p300/AR axis may present a promising therapeutic approach for treating PCOS.
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PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Jiaxing Huang,Xiaotang Wang,Na Li,Wei Fan,Xingran Li,Qian Zhou,Jiangyi Liu,Wanqian Li,Zhi Zhang,Xiaoyan Liu,Shuhao Zeng,Hui Yang,Meng Tian,Peizeng Yang,Shengping Hou
Activated microglia in the retina are essential for the development of autoimmune uveitis. Yin-Yang 1 (YY1) is an important transcription factor that participates in multiple inflammatory and immune-mediated diseases. Here, an increased YY1 lactylation in retinal microglia within in the experimental autoimmune uveitis (EAU) group is observed. YY1 lactylation contributed to boosting microglial activation and promoting their proliferation and migration abilities. Inhibition of lactylation suppressed microglial activation and attenuated inflammation in EAU. Mechanistically, cleavage under targets & tagmentation （CUT&Tag） analysis revealed that YY1 lactylation promoted microglial activation by regulating the transcription of a set of inflammatory genes, including STAT3, CCL5, IRF1, IDO1 , and SEMA4D . In addition, p300 is identified as the writer of YY1 lactylation. Inhibition of p300 decreased YY1 lactylation and suppressed microglial inflammation in vivo and in vitro. Collectively, the results showed that YY1 lactylation promoted microglial dysfunction in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation/inflammatory genes axis.
研究领域:
免疫学
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神经科学
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分子生物学
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眼科学
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DOI
PubMed
高影响因子
Cell Death & Disease
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2023
·Vol. 14
·期 4
·1-10
·
IF 9
Xia Kangkai,Li Shujing,Yang Yuxi,Shi Xiaoxia,Zhao Binggong,Lv Linlin,Xin Zhiqiang,Kang Jie,Ren Ping,Wu Huijian
Breast cancer is the most commonly diagnosed cancer, and its global impact is increasing. Its onset and progression are influenced by multiple cues, one of which is the disruption of the internal circadian clock. Cryptochrome 2 (Cry2) genetic dysregulation may lead to the development of some diseases and even tumors. In addition, post-translational modifications can alter the Cry2 function. Here, we aimed to elucidate the post-translational regulations of Cry2 and its role in breast cancer pathogenesis. We identified p300-drived acetylation as a novel Cry2 post-translational modification, which histone deacetylase 6 (HDAC6) could reverse. Furthermore, we found that Cry2 inhibits breast cancer proliferation, but its acetylation impairs this effect. Finally, bioinformatics analysis revealed that genes repressed by Cry2 in breast cancer were mainly enriched in the NF-κB pathway, and acetylation reversed this repression. Collectively, these results indicate a novel Cry2 regulation mechanism and provide a rationale for its role in breast tumorigenesis.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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DOI
PubMed
高影响因子
GENOME BIOLOGY
·
2025
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IF 9.4
Junhui Lv,Zhinang Yin,Conghui Li,Honglin Wen,Jian Ni,Peiyuan Yang,Zemin Song,Ying Xiang,Honghong Wang,Rui Lu,Li Huang,Ying Zhou,Hai-Bing Zhou,Ruijing Xiao,Pingping Fang,Kaiwei Liang
Background KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia (AML) associated with poor prognosis. Despite their strong oncogenic potential, the mechanisms underlying their genomic targeting and leukemogenic function remain unclear. A major challenge has been their large size, which has impeded preclinical model development and mechanistic studies. Results We employ a domain-focused truncation strategy to generate de novo murine models of K/C and K/P fusions, which faithfully recapitulate the morphological, immunophenotypic, and transcriptomic features of KAT6A-rearranged AML. Genomic profiling reveals that KAT6A fusions preferentially localize to H3K4me2/3-marked regions, while biochemical analyses uncover that KAT6A interacts with the Nucleosome Remodeling Factor (NURF), a key H3K4me2/3 reader. Disrupting NURF-chromatin interactions via depletion or small-molecule inhibition of its subunit, Bromodomain PHD Finger Transcription Factor (BPTF), impairs K/C recruitment and disrupts MLL/COMPASS-mediated H3K4me2 deposition, defining a functional epigenetic module involving KAT6A chimeras, NURF, and MLL/COMPASS. Notably, CBP/P300 inhibition reduces histone acetylation and chromatin accessibility, further impairing the recruitment of this epigenetic module. Targeting this module via NURF or CBP/P300 inhibition demonstrates efficacy in K/C leukemia models, with enhanced therapeutic effects observed when combined. Conclusions Our study identifies a self-reinforcing epigenetic module of histone modifiers and readers in KAT6A-rearranged AML, providing mechanistic insights into the genomic targeting of KAT6A chimeras and highlighting promising combinatorial therapeutic strategies. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-025-03743-y.
研究领域:
癌症生物学
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表观遗传学
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基因组学
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分子生物学
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血液学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL ENDODONTIC JOURNAL
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2026
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IF 6.4
Yongjie Cai,Xiaoting Peng,Beichen Chen,Yiqing Zhao,Waruna Lakmal Dissanayaka,Yiwen Zhang,Shengyan Yang,Qiong Xu
Aim To delineate the mechanisms underlying the role of lactate-related lactylation, a novel post-translational modification, in the odontogenic differentiation of human dental pulp stem cells (hDPSCs). Methodology Dynamic levels of key glycolytic enzymes and histone lactylation along odontogenic differentiation in hDPSCs were evaluated by Western Blot and quantitative PCR (qPCR). Odontogenic differentiation was assessed via Alkaline Phosphatase and Alizarin Red S staining after treatment with sodium lactate, both with and without p300 knockdown. CUT&Tag sequencing of histone H3K18 lactylation (H3K18la) was performed, and genes identified through this analysis were subjected to pathway enrichment. WNT5A-knockdown hDPSCs were generated to elucidate the impact of both WNT5A and WNT5A/Ca 2+ signalling axis in odontogenesis. Finally, we validated the critical function of lactylation in dentine regeneration using a subcutaneous ectopic transplantation model in nude mice with and without sodium lactate via intraperitoneal injection. Results The similar dynamic trends were observed in glycolytic enzyme expression, intracellular lactate and lactylation levels in hDPSCs. Exogenous lactate dose-dependently increased H3K18 lactylation and significantly promoted hDPSC odontogenic differentiation. Mechanistically, the key lactyltransferase p300 was demonstrated to be a regulator that enhanced lactate-induced H3K18la modification and odontogenic differentiation in hDPSCs. CUT&Tag sequencing identified WNT5A as a target gene whose promoter exhibited increased H3K18la enrichment upon lactate treatment. Lactate upregulated WNT5A expression and activated the WNT5A/Ca 2+ signalling pathway via p300-mediated H3K18la, consequently accelerating the odontogenic differentiation. Further in vivo evidence revealed that lactate administration promoted pulp-like tissue regeneration, accompanied by increased hDPSC odontogenic marker expression and H3K18la levels in nude mice with subcutaneously transplanted dentine slices. Conclusions The lactate-driven mechanism acts through the p300-mediated H3K18la-WNT5A/Ca 2+ signalling axis to promote the odontogenic differentiation of hDPSCs. The crosstalk between metabolism, epigenetic modifications and signalling pathways of hDPSCs might offer novel strategies for dental pulp regeneration.
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PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2025
·
IF 4.7
Hanghang Wang,Chen Chen,Mingzhen Xue,Yu Zhang,Keming Chen,Bingjie Sun,Peipei Wang,Xinyi Tong,Xiong Yu,Han Li,Jia Li,Lihong Hu,Yi Zang,Linguo Zhao,Xiachang Wang,Yinan Zhang
Gynostemma pentaphyllum ( Thunb. ) Makino has been traditionally utilized as medicinal herb and function food in traditional Chinese medicine for treating chronic hepatic disorders. Sweet variants of G. pentaphyllum collected from different regions of China are cultivated as the primary resources for the preparation of curative products. We and other groups identified a series of dammarane-type triterpenoids enriched in the plant, such as gypenosides LVI and XLVI, as the bioactive components responsible for the hepatoprotective effect. However, their therapeutic potential may be constrained by low oral bioavailability and complex metabolic pathways. This study applied an in vitro analysis of gut microbiome-based metabolism to determine the major pathway of the gypenosides. Structure-activity relationships, pharmacokinetic studies, and pharmacodynamic results revealed that the removal of the C-3 saccharide chain is not only the main metabolic pathway in the intestinal tract but also generates the active hepatoprotective ingredient with higher bioavailability and potency than the proteotype. Notably, the investigation of underlying the mechanism demonstrated that the compounds inhibited the activation of hepatic stellate cells via the AMPK/P300/Smad3 signaling pathway. Collectively, these findings demonstrate that in vivo metabolism is critical for unlocking the therapeutic potential of orally administered sweet variant G. pentaphyllum , as this metabolic process releases active ingredients that overcome the bioavailability limitations of the parent gypenoside.
研究领域:
中药学
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天然产物化学
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肝脏病学
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分子药理学
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药物代谢
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肠道微生物组学
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药代动力学
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产品关联
DOI
PubMed
高影响因子
Cancer Communications
·
2023
·Vol. 43
·期 3
·338-364
·
IF 16.2
Peng Xia,Hao Zhang,Haofeng Lu,Kequan Xu,Xiang Jiang,Yuke Jiang,Xiangdong Gongye,Zhang Chen,Jie Liu,Xi Chen,Weijie Ma,Zhonglin Zhang,Yufeng Yuan
Background Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6-adenosine (METTL5) controls the development of HCC and the Warburg effect. Methods In the current study, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione-S-transferase pulldown, coimmunoprecipitation, RNA sequencing, non-targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. Results We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A ( LDHA ), enolase 1 ( ENO1 ), triosephosphate isomerase 1 ( TPI1 ), solute carrier family 2 member 1 ( SLC2A1 ), and pyruvate kinase M2 ( PKM2 ). The c-Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c-Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient-derived tumor xenograft (PDX) models, adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice. Conclusions These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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转化医学
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产品关联
DOI
PubMed
高影响因子
ELECTROCHIMICA ACTA
·
2020
·
IF 6.215
Qingqing Zhang,Tingting Hao,Dandan Hu,Zhiyong Guo,Sui Wang,Yufang Hu
A new RNA aptamer-involved electrochemiluminescence (ECL) strategy for sensitive detection of histone acetyltransferase (HAT p300) is designed well based on coenzyme A (CoA)-initiated competitive response and advanced DNA nano-biotechnology. For the first time, this interesting analytical process is comprised of significant histone acetylation catalyzed by HAT p300, competitive replacement triggered by the specific binding of CoA and its RNA aptamer , stable scaffold guided by DNA nano-prism and typical amplification managed by hybrid chain reaction (HCR). Upon recognition of the RNA aptamer to CoA generated in acetylation, auxiliary DNA (A-DNA) which can be captured by three hanging arms of the fabricated DNA nano-prism immobilized onto Au electrode surface is released from the aptamer/A-DNA complex. Moreover, A-DNA can also open skillfully one hairpin DNA (H1), then turning into HCR process by alternating hybridization with the other hairpin DNA (H2). Abundant Ru(phen) 3 2+ molecules which have a strong interaction with dsDNA can result in a significant output. This proposed platform exhibits excellent specificity and sensitivity toward HAT p300 with a detection limit of 0.001 nM and takes on outstanding practicality and superiority, which presents a great potential for HAT p300 analysis in biomedical sciences.
研究领域:
分析化学
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生物化学
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分子生物学
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生物医学科学
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产品关联
DOI
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2020
·
IF 7.1
Qingqing Zhang,Dandan Hu,Tianyu Zhan,Yufang Hu,Zhiyong Guo,Sui Wang
A novel Medusa electrochemiluminescence (ECL) immunosensor for quantitative detection of histone acetyltransferase (HAT p300) is designed and built well based on magnetic gold nanoparticles (Au-Fe 3 O 4 NPs), DNA nanonets and terminal deoxynucleotidyl transferase (TdT)-triggered renascent DNAs containing abundant A and T (named as AT-dsDNAs). Firstly, Au-Fe 3 O 4 NPs and substrate peptides are coated with the bare electrode surface one after the other. As the acetylation reaction happens, DNA nanonets, which are synthesized via Y-shape DNA (as building block) and acetyl antibody (Ab Ac )-grafted dsDNA (as crosslinker), are attached on the electrode surface. Next, AT-dsDNAs are formed under NaCl condition by TdT catalysis, in where deoxyadenosine triphosphate (dATP) and deoxythymidine triphosphate (dTTP) (half and half) can be added ceaselessly to countless 3′−OH of DNA nanonets. Abundant Ru(phen) 3 2+ molecules, which can be integrated well into high-level DNA nanomaterials above, serve as ECL luminophore in our biosensing. Only being HAT p300, an outstanding ECL response occurs favorably, and a detection limit of 0.0029 nM is acquired with a linear response in the range of 0.006–60 nM. The Medusa immunosensor with improved sensitivity presents a promising and possible widely use for the HATs-relevant clinical study and drug development.
研究领域:
生物化学
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纳米技术
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分析化学
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生物传感器
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分子生物学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）