R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/MYC/CEBPA signaling.

R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m6A/PFKP/LDHB axis.

R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDHs), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here we show that R-2HG effectively attenuates aerobic glycolysis, a hallmark of cancer metabolism, in (R-2HG-sensitive) leukemia cells. Mechanistically, R-2HG abrogates fat-mass- and obesity-associated protein (FTO)/N6-methyladenosine (m6A)/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated post-transcriptional upregulation of phosphofructokinase platelet (PFKP) and lactate dehydrogenase B (LDHB) (two critical glycolytic genes) expression and thereby suppresses aerobic glycolysis. Knockdown of FTO, PFKP, or LDHB recapitulates R-2HG-induced glycolytic inhibition in (R-2HG-sensitive) leukemia cells, but not in normal CD34+ hematopoietic stem/progenitor cells, and inhibits leukemogenesis in vivo; conversely, their overexpression reverses R-2HG-induced effects. R-2HG also suppresses glycolysis and downregulates FTO/PFKP/LDHB expression in human primary IDH-wild-type acute myeloid leukemia (AML) cells, demonstrating the clinical relevance. Collectively, our study reveals previously unrecognized effects of R-2HG and RNA modification on aerobic glycolysis in leukemia, highlighting the therapeutic potential of targeting cancer epitranscriptomics and metabolism.

MAE-seq refines regulatory elements across the genome.

Proper cell fate determination relies on precise spatial and temporal genome-wide cooperation between regulatory elements (REs) and their targeted genes. However, the lengths of REs defined using different methods vary, which indicates that there is sequence redundancy and that the context of the genome may be unintelligible. We developed a method called MAE-seq (Massive Active Enhancers by Sequencing) to experimentally identify functional REs at a 25-bp scale. In this study, MAE-seq was used to identify 626879, 541617 and 554826 25-bp enhancers in mouse embryonic stem cells (mESCs), C2C12 and HEK 293T, respectively. Using ∼1.6 trillion 25 bp DNA fragments and screening 12 billion cells, we identified 626879 as active enhancers in mESCs as an example. Comparative analysis revealed that most of the histone modification datasets were annotated by MAE-Seq loci. Furthermore, 33.85% (212195) of the identified enhancers were identified as de novo ones with no epigenetic modification. Intriguingly, distinct chromatin states dictate the requirement for dissimilar cofactors in governing novel and known enhancers. Validation results show that these 25-bp sequences could act as a functional unit, which shows identical or similar expression patterns as the previously defined larger elements, Enhanced resolution facilitated the identification of numerous cell-specific enhancers and their accurate annotation as super enhancers. Moreover, we characterized novel elements capable of augmenting gene activity. By integrating with high-resolution Hi-C data, over 55.64% of novel elements may have a distal association with different targeted genes. For example, we found that the Cdh1 gene interacts with one novel and two known REs in mESCs. The biological effects of these interactions were investigated using CRISPR-Cas9, revealing their role in coordinating Cdh1 gene expression and mESC proliferation. Our study presents an experimental approach to refine the REs at 25-bp resolution, advancing the precision of genome annotation and unveiling the underlying genome context. This novel approach not only advances our understanding of gene regulation but also opens avenues for comprehensive exploration of the genomic landscape.

Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally.

DNA and histone modifications have notable effects on gene expression1. Being the most prevalent internal modification in mRNA, the N6-methyladenosine (m6A) mRNA modification is as an important post-transcriptional mechanism of gene regulation2-4 and has crucial roles in various normal and pathological processes5-12. However, it is unclear how m6A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m6A deposition globally. We show that m6A modifications are enriched in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m6A methyltransferase complex (MTC), which in turn facilitates the binding of the m6A MTC to adjacent RNA polymerase II, thereby delivering the m6A MTC to actively transcribed nascent RNAs to deposit m6A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m6A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m6A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation.

Fluorescence Enhancement of CdS:Ag Quantum Dots Co-Assembled with Au Nanoparticles in a Hollow Nanosphere Form.

Colloidal quantum dots (QDs) have exceptional fluorescence properties. Overcoming aggregation-induced quenching and enhancing the fluorescence of colloidal QDs have remained a challenging issue in this field. In this study, composite hollow nanospheres composed of Au nanoparticles (NPs) and CdS:Ag-doped QDs were successfully constructed through controlled microemulsion-based cooperative assembly. This method harnessed the localized surface plasmon resonance (LSPR) effect of Au NPs nearby doped QDs, resulting in enhanced doped QD fluorescence and the observation of the Purcell effect. The composite hollow nanospheres show a fluorescence enhancement compared to that of the pure CdS:Ag QDs. The enhanced fluorescence was demonstrated to come from the synergetic enhancement of the absorption and emission transition of the doped QDs. This approach provides a feasible technological pathway to address the challenge of improving the fluorescence performance of the doped QDs.

Influenza A (H1N1) virus induced long-term remission in a refractory acute myeloid leukaemia.

There have been reports of haematological cancer patients achieving spontaneous remission after being infected with the influenza A or SARS-COV-2 virus. Here, we present the first case of long-term complete remission (CR) induced by influenza A (IAV, H1N1 subtype) in a refractory AML patient and have functionally validated this finding in two different animal disease models. We observed a significant increase in the proportion of helper T cells in the patient after IAV infection. The levels of cytokines, including IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF-α, were higher in IAV-infected patients compared with control groups. These findings indicate that the anti-tumour effects induced by IAV are closely related to the modification of the immune response. Our study provides new evidence of the anti-tumour effects of IAV from a clinical practice perspective.

Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression.

Glutamine metabolic reprogramming in acute myeloid leukaemia (AML) cells contributes to the decreased sensitivity to antileukemic drugs. Leukaemic cells, but not their myeloid counterparts, largely depend on glutamine. Glutamate dehydrogenase 1 (GDH1) is a regulation enzyme in glutaminolysis. However, its role in AML remains unknown. Here, we reported that GDH1 was highly expressed in AML: high GDH1 was one of the independent negative prognostic factors in AML cohort. The dependence of leukaemic cells on GDH1 was proved both in vitro and in vivo. High GDH1 promoted cell proliferation and reduced survival time of leukaemic mice. Targeting GDH1 eliminated the blast cells and delayed AML progression. Mechanistically, GDH1 knockdown inhibited glutamine uptake by downregulating SLC1A5. Moreover, GDH1 invalidation also inhibited SLC3A2 and abrogated the cystine-glutamate antiporter system Xc- . The reduced cystine and glutamine disrupted the synthesis of glutathione (GSH) and led to the dysfunction of glutathione peroxidase-4 (GPX4), which maintains the lipid peroxidation homeostasis by using GSH as a co-factor. Collectively, triggering ferroptosis in AML cells in a GSH depletion manner, GDH1 inhibition was synthetically lethal with the chemotherapy drug cytarabine. Ferroptosis induced by inhibiting GDH1 provides an actionable therapeutic opportunity and a unique target for synthetic lethality to facilitate the elimination of malignant AML cells.

circSLC25A13 acts as a ceRNA to regulate AML progression via miR-616-3p/ADCY2 axis.

Circular RNAs (circRNAs), a type of endogenous noncoding RNA (ncRNA), exert vital roles in leukemia progression and are promising prognostic factors. Here, we report a novel circRNA, circSLC25A13 (hsa_circ_0081188), which was increased in acute myeloid leukemia (AML) patients with poor overall survival (OS) comparing to patients with good prognosis. Knockdown of circSLC25A13 in AML cells inhibited proliferation and increased cell apoptosis in vitro and in vivo. Enhanced circSLC25A13 expression promoted the survival of AML cells. Mechanistically, circSLC25A13 played as a microRNA sponge of miR-616-3p, which inhibited the expression of adenylate cyclase 2 (ADCY2). Downregulation of miR-616-3p and overexpression of ADCY2 partially rescued circSLC25A13 deficient induced cell growth arrest. In summary, through competitive absorption of miR-616-3p and thereby upregulating ADCY2 expression, circSLC25A13 promoted AML progression. Moreover, circSLC25A13 may represent a potential novel biomarker for the prognosis of AML and offer a potential therapeutic target for AML treatment.

Spermatogenesis associated serine rich 2 like plays a prognostic factor and therapeutic target in acute myeloid leukemia by regulating the JAK2/STAT3/STAT5 axis.

BACKGROUND: Spermatogenesis associated serine rich 2 like (SPATS2L) was highly expressed in homoharringtonine (HHT) resistant acute myeloid leukemia (AML) cell lines. However, its role is little known in AML. The present study aimed to investigate the function of SPATS2L in AML pathogenesis and elucidate the underlying molecular mechanisms. METHODS: Overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) were used to evaluate the prognostic impact of SPATS2L for AML from TCGA database and ourcohort. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. The changes of proteins were assessed by Western blot(WB). A xenotransplantation mice model was used to evaluate in vivo growth and survival. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML. RESULTS: SPATS2L expression increased with increasing resistance indexes(RI) in HHT-resistant cell lines we had constructed. Higher SPATS2L expression was observed in intermediate/high-risk patients than in favorable patients. Meanwhile, decreased SPATS2L expression was observed in AML patients achieving complete remission (CR). Multivariate analysis showed high SPATS2L expression was an independent poor predictor of OS, EFS, RFS in AML. SPATS2L knock down (KD) suppressed cell growth, induced apoptosis, and suppressed key proteins of JAK/STAT pathway, such as JAK2, STAT3, STAT5 in AML cells. Inhibiting SPATS2L expression markedly enhanced the pro-apoptotic effects of traditional chemotherapeutics (Ara-c, IDA, and HHT). CONCLUSIONS: High expression of SPATS2L is a poor prognostic factor in AML, and targeting SPATS2L may be a promising therapeutic strategy for AML patients.

In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries.

USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, multiple linear regression, and Naive Bayesian models were constructed using 543 compounds and used to analyze marine compounds. After selecting 240 small molecules for molecular docking with Maestro, MOE, and GOLD, better small molecules than the positive compound P217564 were screened. The molecular structure of "1, 2-dibromobenzene" was optimized to improve the binding effect of the protein, and 10 optimized compounds in ADMET performed well during the screening process. To study the dynamic combination of protein-ligand effect consistency with static molecular docking, 100ns molecular dynamics simulations of candidate compound 1008-1, reference compound P217564, and negative-positive GNE2917 were conducted. The results of molecular docking and molecular dynamics simulation analysis showed that compound 1008-1 maintained a stable conformation with the target protein. Thus, the comprehensive analysis suggests that compound 1008-1 could provide new possibilities for USP7 covalent inhibitor candidates.

Characterization of trichome-specific BAHD acyltransferases involved in acylsugar biosynthesis in Nicotiana tabacum.

Glandular trichomes of tobacco (Nicotiana tabacum) produce blends of acylsucroses that contribute to defence against pathogens and herbivorous insects, but the mechanism of assembly of these acylsugars has not yet been determined. In this study, we isolated and characterized two trichome-specific acylsugar acyltransferases that are localized in the endoplasmic reticulum, NtASAT1 and NtASAT2. They sequentially catalyse two additive steps of acyl donors to sucrose to produce di-acylsucrose. Knocking out of NtASAT1 or NtASAT2 resulted in deficiency of acylsucrose; however, there was no effect on acylsugar accumulation in plants overexpressing NtASAT1 or NtASAT2. Genomic analysis and profiling revealed that NtASATs originated from the T subgenome, which is derived from the acylsugar-producing diploid ancestor N. tomentosiformis. Our identification of NtASAT1 and NtASAT2 as enzymes involved in acylsugar assembly in tobacco potentially provides a new approach and target genes for improving crop resistance against pathogens and insects.

Minimal residual disease level determined by flow cytometry provides reliable risk stratification in adults with T-cell acute lymphoblastic leukaemia.

Minimal residual disease (MRD) is an important independent prognostic factor for relapse and survival in acute lymphoblastic leukaemia (ALL). Compared with adult B-cell ALL, reports of adult T-cell ALL (T-ALL) MRD have been scarce and mostly based on molecular methods. We evaluated the prognostic value of multiparameter flow cytometry (FCM)-based MRD at the end of induction (EOI-MRD). The present retrospective study included 94 adult patients with T-ALL. MRD was detected by six- to eight-colour FCM. Patients who were EOI-MRD positive had a higher cumulative incidence of relapse (CIR) (87·6% vs. 38·8%, P = 0·0020), and a lower relapse-free survival (RFS) (5·4% vs. 61·0%, P = 0·0005) and overall survival (OS) (32·7% vs. 69·7%, P < 0·0001) than those who were EOI-MRD negative. Moreover, for patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) at their first remission, EOI-MRD positivity was predictive of post-transplant relapse (2-year CIR: 68·2% vs. 4·0%, P = 0·0003). Multivariate analysis showed that EOI-MRD was an independent prognostic factor for CIR [hazard ratio (HR) 2·139, P = 0·046], RFS (HR 2·125, P = 0·048) and OS (HR 2·987, P = 0·017). In conclusion, EOI-MRD based on FCM was an independent prognostic factor for relapse and survival in adult T-ALL. For patients who underwent HSCT, EOI-MRD could be used to identify patients with a high risk of relapse after allo-HSCT.

CDKN2A deletions are associated with poor outcomes in 101 adults with T-cell acute lymphoblastic leukemia.

The identification of genetic risk subgroups of T-cell acute lymphoblastic leukemia (T-ALL) may provide evidence for risk stratification and individualized treatment. We investigated the characteristics and prognostic value of tumor suppressor gene CDKN2A deletions in 101 patients with T-ALL. The CDKN2A deletion was present in 23% (23/101) of T-ALL by fluorescence in situ hybridization (FISH). The most common type of CDKN2A deletion was homozygous deletion (70%, 16/23). A lower frequency of CDKN2A deletion was found in patients with early T-cell precursor (ETP) ALL than in patients with non-ETP-ALL (10.4% vs 34.0%; P = .008). Deletion of CDKN2A was significantly associated with younger age (P = .001), higher white blood cell (WBC) count (P < .001) and higher lactate dehydrogenase (LDH) level (P = .002). Patients with CDKN2A deletion had lower 2-year overall survival (OS) and event-free survival (EFS) rates than patients without CDKN2A deletion (2-year OS: 18.6% ± 8.9% vs 47.4% ± 6.2%, P = .032; EFS: 16.4 ± 8.3 vs 38.6 ± 5.9%, P = .022). In multivariable analysis, CDKN2A deletion was an independent adverse prognostic factor for OS (P = .016). In conclusion, adult T-ALL patients with CDKN2A deletion had a poor prognosis, and these patients might benefit from intensive chemotherapy or allogeneic hematopoietic stem-cell transplantation.

Homoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC.

Homoharringtonine, a plant alkaloid, has been reported to suppress protein synthesis and has been approved by the US Food and Drug Administration for the treatment of chronic myeloid leukemia. Here we show that in acute myeloid leukemia (AML), homoharringtonine potently inhibits cell growth/viability and induces cell cycle arrest and apoptosis, significantly inhibits disease progression in vivo, and substantially prolongs survival of mice bearing murine or human AML. Strikingly, homoharringtonine treatment dramatically decreases global DNA 5-hydroxymethylcytosine abundance through targeting the SP1/TET1 axis, and TET1 depletion mimics homoharringtonine's therapeutic effects in AML. Our further 5hmC-seq and RNA-seq analyses, followed by a series of validation and functional studies, suggest that FLT3 is a critical down-stream target of homoharringtonine/SP1/TET1/5hmC signaling, and suppression of FLT3 and its downstream targets (e.g. MYC) contributes to the high sensitivity of FLT3-mutated AML cells to homoharringtonine. Collectively, our studies uncover a previously unappreciated DNA epigenome-related mechanism underlying the potent antileukemic effect of homoharringtonine, which involves suppression of the SP1/TET1/5hmC/FLT3/MYC signaling pathways in AML. Our work also highlights the particular promise of clinical application of homoharringtonine to treat human AML with FLT3 mutations, which accounts for more than 30% of total cases of AML.

Correction to: The m6A eraser FTO facilitates proliferation and migration of human cervical cancer cells.

[This corrects the article DOI: 10.1186/s12935-019-1045-1.].

The m6A eraser FTO facilitates proliferation and migration of human cervical cancer cells.

BACKGROUND: Since FTO was recognized as the first m6A demethylase, the understanding of its biological function has been widely expanded. However, the role of FTO in cervical cancer tumorigenesis remains unclear. METHODS: In this study, we first analyzed the expression of FTO in two independent human cancer datasets and evaluated the correlation between FTO level and cervical cancer progression. Using small hairpin RNA technology, we explored the function of FTO in cervical cancer cell line Hela and SiHa cells, respectively. We then determined the FTO targets by performing transcriptional profile with FTO deficient and competent Hela cells, and finally validated these targets with ribosome profiling and functional rescue experiments. RESULTS: Our data suggested that FTO was frequently overexpressed in human cervical cancer tissues and highly correlated with cervical cancer progression. FTO serves as an oncogenic regulator for cervical cancer cells' proliferation and migration which is vastly depended on its demethylase activity. Mechanistically, FTO interacts with transcripts of E2F1 and Myc, inhibition of FTO significantly impairs the translation efficiency of E2F1 and Myc, however, either overexpress E2F1 or Myc sufficiently compensates the FTO deficiency which decreases cell proliferation and migration. CONCLUSIONS: Our study indicates that FTO plays important oncogenic role in regulating cervical cancer cells' proliferation and migration via controlling m6A modification of E2F1 and Myc transcripts. FTO represents a potential drug candidate for cervical cancer therapy.

Synthesis and structure-activity relationship studies of phenolic hydroxyl derivatives based on quinoxalinone as aldose reductase inhibitors with antioxidant activity.

To enhance aldose reductase (ALR2) inhibition and add antioxidant ability, phenolic hydroxyl was introduced both to the quinoxalinone core and C3 side chain, resulting in a series of derivatives as ALR2 inhibitors. Biological activity tests suggested that most of the derivatives were potent and selective inhibitors with IC50 values ranging from 0.059 to 6.825µM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetic acid (6b) was the most active. Particularly, it was encouraging to find that some derivatives endowed with obvious antioxidant activity, and among them the phenolic 3,4-dihydroxyl compound 6f with 7-hydroxyl in the quinoxalinone core showed the most potent activity, even comparable with the well-known antioxidant Trolox. Structure-activity relationship and docking studies highlighted the importance of phenolic hydroxyl both in C3 side chain and the core structure for constructing potent ALR2 inhibitors with antioxidant activity.

The advancement of polysaccharides in disease modulation: Multifaceted regulation of programmed cell death.

Programmed cell death (PCD), also known as regulatory cell death (RCD), is a process that occurs in all organisms and is closely linked to both normal physiological processes and disease states. Various signaling pathways, such as TP53, KRAS, NOTCH, hypoxia, and metabolic reprogramming, have been found to regulate RCD. Polysaccharides, which are essential natural products, have been the subject of extensive research in the fields of food, nutrition, and medicine due to their wide range of pharmacological effects. Studies have shown that polysaccharides have biological activities and the potential to target signal transduction pathways for the treatment of diseases. This paper provides a review of the mechanisms through which polysaccharides exert their therapeutic effects at different levels and explores the relationship between different types of RCD and human diseases. The aim of this review is to provide a theoretical basis for the further clinical use and application of polysaccharide bioactivities.

High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.

Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

Tomato LysM receptor kinase 4 mediates chitin-elicited fungal resistance in both leaves and fruit.

Fungal infection is a major cause of crop and fruit losses. Recognition of chitin, a component of fungal cell walls, endows plants with enhanced fungal resistance. Here, we found that mutation of tomato LysM receptor kinase 4 (SlLYK4) and chitin elicitor receptor kinase 1 (SlCERK1) impaired chitin-induced immune responses in tomato leaves. Compared with the wild type, sllyk4 and slcerk1 mutant leaves were more susceptible to Botrytis cinerea (gray mold). SlLYK4 extracellular domain showed strong binding affinity to chitin, and the binding of SlLYK4 induced SlLYK4-SlCERK1 association. Remarkably, qRT-PCR analysis indicated that SlLYK4 was highly expressed in tomato fruit, and ß-GLUCURONIDASE (GUS) expression driven by the SlLYK4 promoter was observed in tomato fruit. Furthermore, SlLYK4 overexpression enhanced disease resistance not only in leaves but also in fruit. Our study suggests that chitin-mediated immunity plays a role in fruit, providing a possible way to reduce fungal infection-related fruit losses by enhancing the chitin-induced immune responses.