Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission

Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells.Pharmacological induction of excessively asymmetric mitofissionassociated cell death(MFAD)by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy.By screening a series of paninhibitors,we identified pracinostat,a pan-histone deacetylase(HDAC)inhibitor,as a novel MFAD inducer,that exhibited a significant anticancer effect on colorectal cancer(CRC)in vivo and in vitro.Pracinostat increased the expression of cyclin-dependent kinase 5(CDK5)and induced its acetylation at residue lysine 33,accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynaminrelated protein 1(Drp1)-mediated mitochondrial peripheral fission.CRC cells with high level of CDK5(CDK5-high)displayed midzone mitochondrial division that was associated with oncogenic phenotype,but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells.Mechanistically,pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor(MFF)to mitochondrial fission 1 protein(FIS1).Thus,our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells,which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.

Alteration of mitochondrial protein succinylation against cellular oxidative stress in cancer

Dear Editor,Lysine residue succinylation is a novel post-translational modification that recently attracted extensive attention.Succinylation is achieved by non-enzymatic processes or by a series of enzymes[like p300,lysine acetyltransferase 2A(KAT2A)]that transfer the succinyl groups from succinyl-coenzyme A(CoA)to the specific lysine,modulating protein function in various physiological processes[1].As a high-energy metabolite,succinyl-CoA is mainly produced within the mitochondrial matrix and peroxisomes.Its high-rate generation in the tricarboxylic acid(TCA)cycle and its impermeability across the mitochondrial inner membrane(due to its negative charge property)enhance succinyl-CoA accumulation within mitochondria.

GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer

Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

Copy number variation of NAL23 causes narrow-leaf development in rice

Leaf shape is a key trait for plant architecture relating to photosynthesis and transpiration in plants(Lawson et al.,2020).Erect leaves with proper leaf length and width,particularly the upper three leaves in cereal crops,could significantly improve light absorption efficiency in canopy and ultimately increase crop yield(Jiao et al.,2010).Rice leaves initiate at the peripheral zone of shoot apical meristem,then develop along the proximal-distal,adaxial-abaxial,and mediallateral axes to form a flat symmetric architecture(Du et al.,2018).

Identification of miR-515-3p and its targets,vimentin and MMP3,as a key regulatory mechanism in esophageal cancer metastasis:functional and clinical significance

Metastasis is the main factor of treatment failure in cancer patients,but the underlying mechanism remains to be elucidated and effective new treatment strategies are urgently needed.This study aims to explore novel key metastasis-related microRNAs(miRNAs)in esophageal squamous cell carcinoma(ESCC).By comparing miRNA profiles of the highly metastatic ESCC cell sublines,we established through serial in vivo selection with the parental cells,we found that the expression level of miR-515-3p was lower in ESCC tumor tissues than adjacent normal tissues,further decreased in metastatic tumors,and moreover,markedly associated with advanced stage,metastasis and patient survival.The in vitro and in vivo assays suggested that miR-515-3p could increase the expression of the epithelial markers as well as decrease the expression of the mesenchymal markers,and more importantly,suppress invasion and metastasis of ESCC cells.Mechanistically,we revealed that miR-515-3p directly regulated vimentin and matrix metalloproteinase-3(MMP3)expression by binding to the coding sequence and 3′untranslated region,respectively.In addition,the data from whole-genome methylation sequencing and methylation-specific PCR indicated that the CpG island within miR-515-3p promoter was markedly hypermethylated in ESCC cell lines and ESCC tumor tissues,which may lead to deregulation of miR-515-3p expression in ESCC.Furthermore,our preclinical experiment provides solid evidence that systemic delivery of miR-515-3p oligonucleotide obviously suppressed the metastasis of ESCC cells in nude mice.Taken together,this study demonstrates that miR-515-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic strategy in ESCC.

Genome-wide identification of key regulatory lncRNAs in esophageal cancer metastasis

Dear Editor,Metastasis leads to a poor prognosis of patients with esophageal squamous cell carcinoma(ESCC).1-3 but the study on cancer metastasis has been hampered by a lack of reliable cell and animal models.Systematic identification and functional validation of metastasis-associated long non-coding RNAs(lncRNAs)and microRNAs(miRNAs),as well as-their interactions in ESCC are urgently needed.

Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed.Here,a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs.A series of functional assays showed that desloratadine,an antiallergic drug,can repress proliferation in HCC cell lines,cell-derived xenograft(CDX),patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.N-myristoyl transferase 1(NMT1)was identified as a target protein of desloratadine by drug affinity responsive target stability(DARTS)and surface plasmon resonance(SPR)assays.Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo.Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3(VILIP3)was a new substrate of NMT1 in protein N-myristoylation modification,and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC.Mechanistically,desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity,disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling.Conclusively,this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.

Small-molecule agents for cancer immunotherapy

Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner

As one of the hallmarks of cancer,metabolic reprogramming leads to cancer progression,and targeting glycolytic enzymes could be useful strategies for cancer therapy.By screening a small molecule library consisting of 1320 FDA-approved drugs,we found that penfluridol,an antipsychotic drug used to treat schizophrenia,could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma(ESCC).Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol.By using drug affinity responsive target stability(DARTS)technology and proteomics,we identified phosphofructokinase,liver type(PFKL),a key enzyme in glycolysis,as a direct target of penfluridol.Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells,illustrating that PFKL is essential for the bioactivity of penfluridol.High PFKL expression is correlated with advanced stages and poor survival of ESCC patients,and silencing of PFKL significantly suppressed tumor growth.Mechanistically,direct binding of penfluridol and PFKL inhibits glucose consumption,lactate and ATP production,leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner.Taken together,PFKL is a potential prognostic biomarker and therapeutic target in ESCC,and penfluridol may be a new therapeutic option for management of this lethal disease.

ISGylation orchestrates the degradation flux of cellular cargo toward lysosome

Post-translational modification(PTM)is a critical step for nascent protein processing,which accompanies with proteins lifetime to modulate their functions dynamically.Currently,there are over 300 species of PTMs been identified,including chemical group modification(e.g.,phosphate,acetyl,methyl,or succinyl groups)and ubiquitin-like(UBL)group modification(e.g.,ubiquitination,SUMOylation,and ISGylation).

Advances in targeted therapy for esophageal cancer

Esophageal cancer(EC)is one of the most lethal cancers in the world,and its morbidity and mortality rates rank among the top ten in China.Currently,surgical resection,radiotherapy and chemotherapy are the primary clinical treatments for esophageal cancer.However,outcomes are still unsatisfactory due to the limited efficacy and severe adverse effects of conventional treatments.As a new type of approach,targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer;these include cetuximab and bevacizumab,which target epidermal growth factor receptor(EGFR)and vascular endothelial growth factor(VEGF),respectively.In addition,other drugs targeting surface antigens and signaling pathways or acting on immune checkpoints have been continuously developed.For example,trastuzumab,a monoclonal antibody targeting human epidermal growth factor receptor 2(HER-2),has been approved by the Food and Drug Administration(FDA)as a first-line treatment of HER-2-positive cancer.Moreover,the PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced esophageal squamous cell carcinoma(ESCC).These novel drugs can be used alone or in combination with other treatment strategies to further improve the treatment efficacy and prognosis of cancer patients.Nevertheless,adverse events,optimal dosages and effective combinations still need further investigation.In this review,we expound an outline of the latest advances in targeted therapies of esophageal cancer and the mechanisms of relevant drugs,discuss their efficacy and safety,and provide a clinical rationale for precision medicine in esophageal cancer.

Understanding the proteome encoded by “non-coding RNAs”:new insights into human genome

A great number of non-coding RNAs(ncRNAs) account for the majority of the genome. The translation of these ncRNAs has been noted but seriously underestimated due to both technological and theoretical limitations. Based on the development of ribosome profiling(Ribo-seq), full length translating RNA analysis(RNC-seq) and mass spectrometry technology, more and more ncRNAs are being found to be translated in different organism, and some of them can produce functional peptides. While recently, not only individual new functional proteins, but also a new proteome have been experimentally discovered to be encoded by endogenous lncRNAs and circRNAs. These new proteins are of biological significance, suggesting the connection of the translation of ncRNAs to human physiology and diseases. Therefore, an in-depth and systematic understanding of the coding capabilities of ncRNAs is necessary for basic biology and medicine. In this review, we summarize the advances in the field of discovering this new proteome, i.e. "ncRNA-coded" proteins.

Targeting PI3K/Akt signal transduction for cancer therapy

The phosphatidylinositol 3-kinase(PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers,contributing to the occurrenee and progression of tumors.Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function.Based on accumulating evidenee,strategies targeting major components of the pathway might provide new in sights for can cer drug discovery.Researchers have explored the use of some in hibitors targeti ng this pathway to block survival pathways.However,because oncogenic PI3K pathway activation occurs through various mechanisms,the clinical efficacies of these inhibitors are limited.Moreover,pathway activation is accompanied by the development of therapeutic resista nee.Therefore,strategies involvi ng pathway in hibitors and other can cer treatments in combinati on might solve the therapeutic dilemma.In this review,we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes,review the current statuses of different PI3K/Akt in hibitors,and in troduce combi nation therapies con sisti ng of signaling in hibitors and conven tional cancer therapies.The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway,either alone or in combi nation with other therapies,are the most effective treatment strategy for can cer.

Targeting m6A modification inhibits herpes virus 1 infection

The latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A)modification of viral RNAs affects virus infection are poorly understood.Here,we report that HSV-1 infection enhanced the expression of m6A writers(METTL3,METTL14)and readers(YTHDF1/2/3)at the early infection stage and decreased their expression later on,while suppressed the erasers'(FTO,ALBKH5)expression immediately upon infection to facilitate viral replication.Inhibiting m6A modification by 3-deazaadenosine(DAA)significantly decreased viral replication and reduced viral reproduction over 1000 folds.More interestingly,depleting the writers and readers by siRNAs inhibited virus replication and reproduction;whereas depleting the erasers promoted viral replication and reproduction.Silencing YTHDF3 strikingly decreased viral replication by up to 90%,leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction,respectively.Depletion of m6A initiator METTL3(by 60%–70%)by siRNA correlatedly decreased viral replication 60%–70%,and reduced virus yield over 30-fold.Consistently,ectopic expression of METTL3 largely increased virus yield.METTL3 knockdown suppressed the HSV-1 intermediate early and early genes(ICP0,ICP8 and UL23)and late genes(VP16,UL44,UL49 and ICP47);while ectopic expression of METTL3 upregulated these gene expression.Results from our study shed the lights on the importance for m6A modification to initiate HSV-1 early replication.The components of m6A modification machinery,particularly m6A initiator METTL3 and reader YTHDF3,would be potential important targets for combating HSV-1 infections.

AHA1 upregulates IDH1 and metabolic activity to promote growth and metastasis and predicts prognosis in osteosarcoma

Osteosarcoma(OS)is the most common primary malignant bone tumor in children and adolescents.Although activator of HSP90 ATPase activity 1(AHA1)is reported to be a potential oncogene,its role in osteosarcoma progression remains largely unclear.Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis,the relationship between AHA1 and cancer metabolism is unknown.In this study,we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients.AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo.Mechanistically,AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma.Notably,we identifed that isocitrate dehydrogenase 1(IDH1)is a novel client protein of Hsp90 AHA1.Furthermore,the IDH1 protein level was positively correlated with AHA1 in osteosarcoma.And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma.Moreover,high IDH1 level was also associated with poor prognosis of osteosarcoma patients.This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis,which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.

The Ultrafast and Accurate Mapping Algorithm FANSe3:Mapping a Human Whole-Genome Sequencing Dataset Within 30 Minutes

Aligning billions of reads generated by the next-generation sequencing(NGS)to reference sequences,termed“mapping”,is the time-consuming and computationally-intensive process in most NGS applications.A Fast,accurate and robust mapping algorithm is highly needed.Therefore,we developed the FANSe3 mapping algorithm,which can map a 30×human wholegenome sequencing(WGS)dataset within 30 min,a 50×human whole exome sequencing(WES)dataset within 30 s,and a typical mRNA-seq dataset within seconds in a single-server node without the need for any hardware acceleration feature.Like its predecessor FANSe2,the error rate of FANSe3 can be kept as low as 10-9 in most cases,this is more robust than the Burrows-Wheeler transform-based algorithms.Error allowance hardly affected the identification of a driver somatic mutation in clinically relevant WGS data and provided robust gene expression profiles regardless of the parameter settings and sequencer used.The novel algorithm,designed for high-performance cloud-computing after infrastructures,will break the bottleneck of speed and accuracy in NGS data analysis and promote NGS applications in various fields.The FANSe3 algorithm can be downloaded from the website:http://www.chi-biote ch.com/fanse 3/.

Light-activated nitric-oxide overproduction theranostic nanoplatform based on long-circulating biomimetic nanoerythrocyte for enhanced cancer gas therapy

The limited intratumoral perfusion of nitric oxide(NO)-carrying nanoparticles into solid tumors caused by the inherent biological barriers in vivo greatly attenuates their generated efficacy. Herein, through entrapping heat-sensitive NO donors(BNN6)on mesoporous polydopamine nanoparticles(M-PDA) and subsequently enveloping with red blood cells membranes, a heatresponsive biomimetic theranostic nanoerythrocyte(M/B@R) is developed to boost NO-based cancer therapy. The reserved intact structure of red blood cells membranes(RBCm) endows M/B@R with superior biosafety and stealth properties for prolonged circulation time and subsequent enhanced tumor accumulation. Once internalized in tumors and excited by nearinfrared light(NIR, 808 nm) irradiation, M/B@R can not only yield plenty of heat for photothermal therapy(PTT) but also achieve the overproduction of NO for highly-efficient NO gas therapy due to its high loading capacity and NIR-absorbing property of M-PDA. The generated NO further ensures the formation of ONOO^(-) which possesses remarkable toxicity to tumor as well as alleviating tumor hypoxia. It is found that M/B@R with NIR as the excitation source can significantly induce synthetic lethality to tumors via the hyperthermia, DNA damage and the ease of tumor hypoxia. Simultaneously, M/B@R also exhibits the potential for bimodal fluorescence and photothermal imaging. The RBCm-camouflaged NO delivery nanoplatform with bimodal imaging capability in this work may provide a new combinatorial paradigm to induce PTT/NO for cancer theranostic applications.