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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

Science China Life Sciences 2025年第1期 204-218页

作者： Chen Xiong Hong Ling Yingdan Huang Hanzhi Dong Bangxiang Xie qian hao Xiang Zhou Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Fudan University Department of Oncology Shanghai Medical CollegeFudan University Department of Breast Surgery Fudan University Shanghai Cancer CenterFudan University Department of Oncology First Affiliated Hospital of Nanchang University Beijing Institute of Hepatology Beijing Youan HospitalCapital Medical University Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer CenterFudan University Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology)Institutes of Biomedical SciencesFudan University

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or si RNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D(Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

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The emerging role of long noncoding RNA RMRP in cancer development and targeted therapy

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Cancer Biology & Medicine 2022年第2期19卷 140-146页

作者： qian hao Xiang Zhou Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer CenterFudan UniversityShanghai 200032China Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)Institutes of Biomedical SciencesFudan UniversityShanghai 200032China

The RNA component of mitochondrial RNA-processing endoribonuclease(RMRP)was first described as an entity that cleaved mitochondrial RNA at a priming site of mitochondrial DNA *** long noncoding RNA(lncRNA)was encoded by an evolutionarily conserved nuclear gene that has been characterized in many species,including human,mouse,cattle,zebrafish,toad,and *** was soon learned that RMRP as a component of the RNase MRP complex was also located in the nucleus,and was critical for ribosomal RNA(rRNA)processing,particularly the biosynthesis of 5.8S *** 2001,the first evidence of the role of RMRP in the pathogenesis of human disorders was reported,involving mutations in the RMRP gene,which caused cartilage-hair hypoplasia(CHH)1,a recessively inherited developmental disorder characterized by short stature,hypoplastic anemia,defective immunity,and predisposition to several cancers.

关键词： immunity anemia pathogenesis

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Deciphering cotton genomic variations for"genes to jeans"

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Molecular Plant 2023年第4期16卷 654-656页

作者： qian-hao Zhu CSIRO Agriculture and Food GPO Box 1700CanberraACT 2601Australia

Genomic variation includes inter-and intraspecific *** former is the genetic footprint of species speciation and *** latter is the within-species variation caused by spontaneous mutation that has been maintained through natural and artificial *** interspecific genomic variations of a crop helps us to understand its genetic diversity and evolution *** intraspecific genomic variations and linking them to phenotypic outcomes sheds light on how natural and artificial selection has shaped the crop and provides targets for improving its performance through molecular breeding technologies.

关键词： breeding artificial linking

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Probabilistic seismic inversion based on physics-guided deep mixture density network

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Petroleum Science 2024年第3期21卷 1611-1631页

作者： qian-hao Sun Zhao-Yun Zong Xin Li National Key Laboratory of Deep Oil and Gas China University of Petroleum(East China)Qingdao266580ShandongChina Laoshan Laboratory Qingdao266580ShandongChina CNOOC Research Institute Ltd. Beijing100028China

Deterministic inversion based on deep learning has been widely utilized in model parameters *** by logging data,seismic data,wavelet and modeling operator,deterministic inversion based on deep learning can establish nonlinear relationships between seismic data and model ***,seismic data lacks low-frequency and contains noise,which increases the non-uniqueness of the *** conventional inversion method based on deep learning can only establish the deterministic relationship between seismic data and parameters,and cannot quantify the uncertainty of *** order to quickly quantify the uncertainty,a physics-guided deep mixture density network(PG-DMDN)is established by combining the mixture density network(MDN)with the deep neural network(DNN).Compared with Bayesian neural network(BNN)and network dropout,PG-DMDN has lower computing cost and shorter training time.A low-frequency model is introduced in the training process of the network to help the network learn the nonlinear relationship between narrowband seismic data and low-frequency *** addition,the block constraints are added to the PG-DMDN framework to improve the horizontal continuity of the inversion *** illustrate the benefits of proposed method,the PG-DMDN is compared with existing semi-supervised inversion *** synthetic data examples of Marmousi II model are utilized to quantify the influence of forward modeling part,low-frequency model,noise and the pseudo-wells number on inversion results,and prove the feasibility and stability of the proposed *** addition,the robustness and generality of the proposed method are verified by the field seismic data.

关键词： Deep learning Probabilistic inversion Physics-guided Deep mixture density network

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Mutant p53 in cancer therapy-the barrier or the path

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Journal of Molecular Cell Biology 2019年第4期11卷 293-305页

作者： Xiang Zhou qian hao Hua Lu Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences and Key Laboratory of Medical Epigenetics and Metabolism Fudan University Shanghai 200032 China Fudan University Shanghai Cancer Center Fudan University Shanghai 200032 China Department of Biochemistry & Molecular Biology and Tulane Cancer Center Tulane University School of Medicine New Orleans LA 70112 USA

Since wild-type p53 is central for maintaining genomic stability and preventing oncogenesis, its coding gene TP53 is highly mutated in ~50% of human cancers, and its activity is almost abrogated in the rest of cancers. Approximately 80% of p53 mutations are single point mutations with several hotspot mutations. Besides loss of function and dominant-negative effect on the wild-type p53 activity, the hotspot p53 mutants also acquire new oncogenic functions, so-called ‘gain-of-functions’(GOF). Because the GOF of mutant p53 is highly associated with late-stage malignance and drug resistance, these p53 mutants have become hot targets for developing novel cancer therapies. In this essay, we review some recent progresses in better understanding of the role of mutant p53 GOF in chemoresistance and the underlying mechanisms, and discuss the pros and cons of targeting mutant p53 for the development of anti-cancer therapies.

关键词： mutant p53 gain-of-function cancer therapy chemoresistance synthetic lethality

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A potential synthetic lethal strategy with PARP inhibitors:perspective on‘Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP’

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Journal of Molecular Cell Biology 2021年第9期13卷 690-692页

作者： qian hao Hua Lu Xiang Zhou Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China Department of Biochemistry&Molecular Biology and Tulane Cancer Center Tulane University School of MedicineNew OrleansLA 70112USA Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer CenterFudan UniversityShanghai 200032China Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)Institutes of Biomedical SciencesFudan UniversityShanghai 200032China

The tumor suppressor p53 plays an important role in the inhibition of cancer progression,particularly in response to chemotherapy or target-specific *** or mutation of p53 often becomes a cancer’s tactic for drug *** of the clinically applied therapeutic strategies is to inhibit poly(ADP-ribose)polymerase(PARP)activity,as PARP inhibitors are widely used for subsets of tumors with homologous recombination deficiency due to mutation of BRCA1/2 or other DNA repair-associated *** has been shown that p53 deficiency or mutation enhances the cytotoxicity of PARP inhibition in various tumors(Williamson et al.,2012).

关键词： suppressor chemotherapy activation

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The LGM refugia of deciduous oak and distribution development since the LGM in China

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Science China Earth Sciences 2023年第1期66卷 80-91页

作者： qian hao Hongyan LIU Ying CHENG Zhaoliang SONG Institute of Surface-Earth System Science School of Earth System ScienceTianjin UniversityTianjin 300072China College of Urban and Environmental Sciences Peking UniversityBeijing 100871China School of Geography and Tourism Shaanxi Normal UniversityXi’an 710119China

The distribution development of oak has significant effects on ecosystems and ***-term forest distribution studies can help to better understand the vegetation dynamics under climate change or human activities in the *** this study,we integrated different methods(i.e.,palaeoecology,phylogeography,and species distribution models)to investigate the likely locations of glacial refugia and the postglacial development of the main deciduous oak species(i.e.,Quercus variabilis,***,***,***,*** and ***).The results indicated that mountains such as the Changbai,Qinling,and Dabie Mountains acted as the refugia in northern and central China during the Last Glacial Maximum(LGM).The present Quercus in northern China could be the result of local dispersal during the postglacial period rather than only that of long-distance migration from south to *** was the main influencing factor for oak migration,while human activities did not show much influence on this widespread *** topography acted as a buffer and made the mountains act as refugia under a deteriorated *** with other main tree genera(e.g.,Pinus and Betula),the refugia locations and migration routes of deciduous oak species were different because of their physiological *** individual migration dynamics of these three genera need to be considered when modelling their dynamics.

关键词： Quercus Pollen analysis Species distribution model Chloroplast DNA Precipitation

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Molecular mechanisms of DNA lesion and repair during antibody somatic hypermutation

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Science China(Life Sciences) 2024年第11期67卷 2344-2353页

作者： qian hao Jinfeng Li Leng-Siew Yeap Shanghai Institute of Immunology Department of Immunology and MicrobiologyState Key Laboratory of Oncogenes and Related GenesShanghai Jiao Tong University School of MedicineShanghai 200025China Center for Immune-Related Diseases at Shanghai Institute of Immunology Department of Endocrinology and Metabolic DiseasesRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China

Antibody diversification is essential for an effective immune response,with somatic hypermutation(SHM)serving as a key molecular process in this ***-induced cytidine deaminase(AID)initiates SHM by inducing DNA lesions,which are ultimately resolved into point mutations,as well as small insertions and deletions(indels).These mutational outcomes contribute to antibody affinity *** mechanisms responsible for generating point mutations and indels involve the base excision repair(BER)and mismatch repair(MMR)pathways,which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to *** this regard,translesion synthesis(TLS)polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA *** review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during *** these mechanisms is critical for elucidating the development of broadly neutralizing antibodies(bnAbs)and autoantibodies,and has implications for vaccine design and therapeutics.

关键词： somatic hypermutation(SHM) insertions and deletions(indels) AID base excision repair(BER) mismatch repair(MMR) translesion synthesis(TLS)polymerases

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The ARTS of p53-dependent mitochondrial apoptosis

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Journal of Molecular Cell Biology 2022年第10期14卷 11-18页

作者： qian hao Jiaxiang Chen Hua Lu Xiang Zhou Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China Department of Physiology Medical College of Nanchang UniversityNanchang 330006China Jiangxi Provincial Key Laboratory of Reproductive Physiology and Pathology Nanchang UniversityNanchang 330006China Department of Biochemistry&Molecular Biology and Tulane Cancer Center Tulane University School of MedicineNew OrleansLA 70112USA Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer CenterFudan UniversityShanghai 200032China Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)Institutes of Biomedical SciencesFudan UniversityShanghai 200032China

The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death,including apoptosis,through transcription-dependent and transcription-independent *** the one hand,nuclear p53 transcriptionally activates the expression of a myriad of pro-apoptotic BCL-2 family genes,such as NOXA,PUMA,BID,BAD,BIK,BAX,etc.,whereas it inactivates the expression of anti-apoptotic BCL-2,BCL-XL,and MCL1,leading to mitochondrial *** the other hand,cytoplasmic p53 also promotes mitochondrial apoptosis by directly associating with multiple BCL-2 family proteins in the ***-related protein in TGF-βsignaling pathway(ARTS),a mitochondria-localized pro-apoptotic protein encoded by an alternative spliced variant of the SEPT4 gene,triggers apoptosis by facilitating proteasomal degradation of BCL-2 and XIAP upon pro-apoptotic *** recently identified SEPT4/ARTS as a new p53 target gene in response to genotoxic *** in turn binds to p53,drives its mitochondrial localization,and enhances the interaction between p53 and BCL-XL,thereby promoting mitochondrial *** review will illustrate the mechanisms of p53-induced mitochondrial apoptosis,offer some recently discovered new insights into the functions of ARTS in regulating mitochondrial cell death,and discuss the clinical significance of ARTS in cancer and non-cancer diseases.

关键词： p53 ARTS SEPT4 BCL-2 family apoptosis cancer therapy

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Comparative Study of Single-phase Phase-locked Loops for Grid-connected Inverters Under Non-ideal Grid Conditions

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CSEE Journal of Power and Energy Systems 2022年第1期8卷 155-164页

作者： Jinming Xu hao qian Shenyiyang Bian Yuan Hu Shaojun Xie Nanjing University of Aeronautics and Astronautics Nanjing 211106China

In renewable power generation systems,ensuring the synchronization of the inverter and the power grid is crucial for the stable operation of grid-connected ***,the phase-locked loop(PLL)technology has become a widely used grid synchronization method because of its simple implementation and robustness under various grid *** though a lot of PLLs have been proposed,an overview and comparative analysis of multiple PLLs can be helpful for practical *** addition,the weak grid condition is a great challenge for the ***,this study first presents an overview of the existing PLLs together with their general structures and basic working *** on the implementation of the phase detector,the PLL can be divided into three categories:power-based PLL(pPLL),orthogonal-signalgenerator-based PLL(OSG-PLL)and adaptive-filter-based PLL(AF-PLL).Then,from the above classification,seven typical single-phase PLLs are selected for further ***,some test results are given,and a comprehensive evaluation of the selected PLLs under different grid conditions is conducted.

关键词： Grid synchronization non-ideal grid condition overview single-phase phase-locked loop(PLL)

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