Discovery of Biphenyl Derivatives to Target Hsp70-Bim Protein-Protein Interaction in Chronic Myeloid Leukemia by Scaffold Hopping Strategy.

Hsp70-Bim protein-protein interaction (PPI) is the most recently identified specific target in chronic myeloid leukemia (CML) therapy. Herein, we developed a new class of Hsp70-Bim PPI inhibitors via scaffold hopping of S1g-10, the most potent Hsp70-Bim PPI inhibitor thus far. Through structure-activity relationship (SAR) study, we obtained a biphenyl scaffold compound JL-15 with a 5.6-fold improvement in Hsp70-Bim PPI suppression (Kd = 123 vs 688 nM) and a 4-fold improvement in water solubility (29.42 vs 7.19 µg/mL) compared to S1g-10. It maintains comparable apoptosis induction capability with S1g-10 against both TKI-sensitive and TKI-resistant CML cell lines in an Hsp70-Bim-dependent manner. Additionally, through SAR, 1H-15N TRSOY-NMR, and molecular docking, we revealed that Lys319 is a "hot spot" in the Hsp70-Bim PPI interface. Collectively, these results provide a novel chemical scaffold and structural insights for the rational design of Hsp70-Bim PPI inhibitors.

Reprogrammed IDO-Induced Immunosuppressive Microenvironment Synergizes with Immunogenic Magnetothermodynamics for Improved Cancer Therapy.

Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.

Nanomaterials in modulating tumor-associated macrophages and enhancing immunotherapy.

Tumor-associated macrophages (TAMs) are predominantly present in the tumor microenvironment (TME) and play a crucial role in shaping the efficacy of tumor immunotherapy. These TAMs primarily exhibit a tumor-promoting M2-like phenotype, which is associated with the suppression of immune responses and facilitation of tumor progression. Interestingly, recent research has highlighted the potential of repolarizing TAMs from an M2 to a pro-inflammatory M1 status-a shift that has shown promise in impeding tumor growth and enhancing immune responsiveness. This concept is particularly intriguing as it offers a new dimension to cancer therapy by targeting the tumor microenvironment, which is a significant departure from traditional approaches that focus solely on tumor cells. However, the clinical application of TAM-modulating agents is often challenged by issues such as insufficient tumor accumulation and off-target effects, limiting their effectiveness and safety. In this regard, nanomaterials have emerged as a novel solution. They serve a dual role: as delivery vehicles that can enhance the accumulation of therapeutic agents in the tumor site and as TAM-modulators. This dual functionality of nanomaterials is a significant advancement as it addresses the key limitations of current TAM-modulating strategies and opens up new avenues for more efficient and targeted therapies. This review provides a comprehensive overview of the latest mechanisms and strategies involving nanomaterials in modulating macrophage polarization within the TME. It delves into the intricate interactions between nanomaterials and macrophages, elucidating how these interactions can be exploited to drive macrophage polarization towards a phenotype that is more conducive to anti-tumor immunity. Additionally, the review explores the burgeoning field of TAM-associated nanomedicines in combination with tumor immunotherapy. This combination approach is particularly promising as it leverages the strengths of both nanomedicine and immunotherapy, potentially leading to synergistic effects in combating cancer.

Intracellular Magnetic Hyperthermia Enables Concurrent Down-Regulation of CD47 and SIRPα To Potentiate Antitumor Immunity.

Harnessing the potential of tumor-associated macrophages (TAMs) to engulf tumor cells offers promising avenues for cancer therapy. Targeting phagocytosis checkpoints, particularly the CD47-signal regulatory protein α (SIRPα) axis, is crucial for modulating TAM activity. However, single checkpoint inhibition has shown a limited efficacy. In this study, we demonstrate that ferrimagnetic vortex-domain iron oxide (FVIO) nanoring-mediated magnetic hyperthermia effectively suppresses the expression of CD47 protein on Hepa1-6 tumor cells and SIRPα receptor on macrophages, which disrupts CD47-SIRPα interaction. FVIO-mediated magnetic hyperthermia also induces immunogenic cell death and polarizes TAMs toward M1 phenotype. These changes collectively bolster the phagocytic ability of macrophages to eliminate tumor cells. Furthermore, FVIO-mediated magnetic hyperthermia concurrently escalates cytotoxic T lymphocyte levels and diminishes regulatory T cell levels. Our findings reveal that magnetic hyperthermia offers a novel approach for dual down-regulation of CD47 and SIRPα, reshaping the tumor microenvironment to stimulate immune responses, culminating in significant antitumor activity.

Separation of high-purity plasma extracellular vesicles for investigating proteomic signatures in diabetic retinopathy.

Extracellular vesicles (EVs) play a multifaceted role in intercellular communication and hold significant promise as bio-functional indicators for clinical diagnosis. Although plasma samples represent one of the most critical sources of circulating EVs, the existing technical challenges associated with plasma-EV isolation have restricted their application in disease diagnosis and biomarker discovery. In this study, we introduce a two-step purification method utilizing ultracentrifugation (UC) to isolate crude extracellular vesicle (EV) samples, followed by a phospholipid affinity-based technique for the selective isolation of small EVs, ensuring a high level of purity for downstream proteomic analysis. Our research demonstrates that the UC & TiO2-coated magnetic bead (TiMB) purification system significantly improves the purity of EVs when compared to conventional UC or TiMB along. We further revealed that proteomic alterations in plasma EVs effectively reflect key gene ontology components associated with diabetic retinopathy (DR) pathogenesis, including the VEGF-activated neuropilin pathway, positive regulation of angiogenesis, angiogenesis, cellular response to vascular endothelial growth factor stimulus, and immune response. By employing a comprehensive analytical approach, which incorporates both time-series analysis (cluster analysis) and differential analysis, we have identified three potential protein signatures including LGALS3, MYH10, and CPB2 that closely associated with the retinopathy process. These proteins exhibit promising diagnostic and severity-classification capabilities for DR disease. This adaptable EV isolation system can be regarded as an effective analytical tool for enhancing plasma-based liquid biopsies toward clinical applications.

Effect of surface modification on the distribution of magnetic nanorings in hepatocellular carcinoma and immune cells.

Magnetic nanomaterial-mediated magnetic hyperthermia is a localized heating treatment modality that has been applied to treat aggressive cancer in clinics. In addition to being taken up by tumor cells to function in cancer therapy, magnetic nanomaterials can also be internalized by immune cells in the tumor microenvironment, which may contribute to regulating the anti-tumor immune effects. However, there exists little studies on the distribution of magnetic nanomaterials in different types of cells within tumor tissue. Herein, ferrimagnetic vortex-domain iron oxide nanorings (FVIOs) with or without the liver-cancer-targeting peptide SP94 have been successfully synthesized as a model system to investigate the effect of surface modification of FVIOs (with or without SP94) on the distribution of tumor cells and different immune cells in hepatocellular carcinoma (HCC) microenvironment of a mouse. The distribution ratio of FVIO-SP94s in tumor cells was 1.3 times more than that of FVIOs. Immune cells in the liver tumor microenvironment took up fewer FVIO-SP94s than FVIOs. In addition, myeloid cells were found to be much more amenable than lymphoid cells in terms of their ability to phagocytose nanoparticles. Specifically, the distributions of FVIOs/FVIO-SP94s in tumor-associated macrophages, dendritic cells, and myeloid-derived suppressor cells were 13.8%/12%, 3.7%/0.9%, and 6.3%/1.2%, respectively. While the distributions of FVIOs/FVIO-SP94s in T cells, B cells, and natural killer cells were 5.5%/0.7%, 3.0%/0.7%, and 0.4%/0.3%, respectively. The results described in this article enhance our understanding of the distribution of nanomaterials in the tumor microenvironment and provide a strategy for rational design of magnetic hyperthermia agents that can effectively regulate anti-tumor immune effects.

Genome Instability and DNA Repair in Somatic and Reproductive Aging.

Genetic material is constantly subjected to genotoxic insults and is critically dependent on DNA repair. Genome maintenance mechanisms differ in somatic and germ cells as the soma only requires maintenance during an individual's lifespan, while the germline indefinitely perpetuates its genetic information. DNA lesions are recognized and repaired by mechanistically highly diverse repair machineries. The DNA damage response impinges on a vast array of homeostatic processes and can ultimately result in cell fate changes such as apoptosis or cellular senescence. DNA damage causally contributes to the aging process and aging-associated diseases, most prominently cancer. By causing mutations, DNA damage in germ cells can lead to genetic diseases and impact the evolutionary trajectory of a species. The mechanisms ensuring tight control of germline DNA repair could be highly instructive in defining strategies for improved somatic DNA repair. They may provide future interventions to maintain health and prevent disease during aging.

Rugby ball-shaped magnetic microcapsule for tumor hyperthermia.

Magnetic hyperthermia (MH) induced by magnetic particles has been widely used to treat tumors. However, the limited heating conversion efficiency inspires the design and synthesis of versatile magnetic materials for enhancing the performance of MH. Herein, we developed rugby ball-shaped magnetic microcapsules as efficient MH agents. The size and shape of the microcapsules can be precisely controlled by adjusting the reaction time and temperature without surfactant assistance. Because of their high saturation magnetization and uniform size/morphology, the microcapsules showed excellent thermal conversion efficiency, with a specific absorption rate of 2391 W g-1. Additionally, we performed in vivo anti-tumor studies on mice and found that MH mediated by magnetic microcapsules effectively inhibited the advancement of hepatocellular carcinoma. The microcapsules' porous structure might allow them to efficiently load different therapeutic drugs and/or functional species. These beneficial properties make microcapsules ideal candidates for medical applications, particularly in disease therapy and tissue engineering.

Reversal of HMGA1-Mediated Immunosuppression Synergizes with Immunogenic Magnetothermodynamic for Improved Hepatocellular Carcinoma Therapy.

Magnetothermodynamic (MTD) therapy can activate antitumor immune responses by inducing potent immunogenic tumor cell death. However, tumor development is often accompanied by multifarious immunosuppressive mechanisms that can counter the efficacy of immunogenic MTD therapy. High-mobility group protein A1 (HMGA1) is overexpressed within hepatocellular carcinoma tissues and plays a crucial function in the generation of immunosuppressive effects. The reversal of HMGA1-mediated immunosuppression could enhance immunogenic tumor cell death-induced immune responses. A ferrimagnetic vortex-domain iron oxide (FVIO) nanoring-based nanovehicle was developed, which is capable of efficiently mediating an alternating magnetic field for immunogenic tumor cell death induction, while concurrently delivering HMGA1 small interfering (si)RNA (siHMGA1) to the cytoplasm of hepatocellular carcinoma Hepa 1-6 cells for HMGA1 pathway interference. Using siHMGA1-FVIO-mediated MTD therapy, the proliferation of hepatocellular carcinoma Hepa 1-6 tumors was inhibited, and the survival of a mouse model was improved. We also demonstrated that siHMGA1-FVIO-mediated MTD achieved synergistic antitumor effects in a subcutaneous hepatocellular carcinoma Hepa 1-6 and H22 tumor model by promoting dendritic cell maturation, enhancing antigen-presenting molecule expression (both major histocompatibility complexes I and II), improving tumor-infiltrating T lymphocyte numbers, and decreasing immunosuppressive myeloid-derived suppressor cells, interleukin-10, and transforming growth factor-ß expression. The nanoparticle system outlined in this paper has the potential to target HMGA1 and, in combination with MTD-induced immunotherapy, is a promising approach for hepatocellular carcinoma treatment.

Inheritance of paternal DNA damage by histone-mediated repair restriction.

How paternal exposure to ionizing radiation affects genetic inheritance and disease risk in the offspring has been a long-standing question in radiation biology. In humans, nearly 80% of transmitted mutations arise in the paternal germline1, but the transgenerational effects of ionizing radiation exposure has remained controversial and the mechanisms are unknown. Here we show that in sex-separated Caenorhabditis elegans strains, paternal, but not maternal, exposure to ionizing radiation leads to transgenerational embryonic lethality. The offspring of irradiated males displayed various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement and aneuploidy. Paternal DNA double strand breaks were repaired by maternally provided error-prone polymerase theta-mediated end joining. Mechanistically, we show that depletion of an orthologue of human histone H1.0, HIS-24, or the heterochromatin protein HPL-1, could significantly reverse the transgenerational embryonic lethality. Removal of HIS-24 or HPL-1 reduced histone 3 lysine 9 dimethylation and enabled error-free homologous recombination repair in the germline of the F1 generation from ionizing radiation-treated P0 males, consequently improving the viability of the F2 generation. This work establishes the mechanistic underpinnings of the heritable consequences of paternal radiation exposure on the health of offspring, which may lead to congenital disorders and cancer in humans.

Porcine IGF-1R synonymous mutations in the extracellular domain affect proliferation and differentiation of skeletal muscle cells.

OBJECTIVE: Miniature pigs are considered ideal organ donors for xenotransplantation in humans, but the mechanism underlying their dwarfism remains to be elucidated. IGF-1R is a crucial factor in body size formation in mammals, including skeletal muscle formation and development. The extracellular domain (ECD) binds to the ligand, a phenomenon that results in the activation of downstream pathways. METHODS: In this study, the coding sequences of two IGF-1R ECD haplotypes of the large Landrace (LP) pig and the small Bama Xiang (BM) pig were cloned into pcDNA3.1 vectors to generate pcDNA3.1-LP and pcDNA3.1-BM. The two recombinant vectors were then transfected into skeletal muscle cells. RESULTS: IGF-1R transcript was found to be expressed at higher levels in the pcDNA3.1-LP group than in the pcDNA3.1-BM group. The IGF-1R ECD from LP promoted cell proliferation and CyclinD1 expression, and promoted the phosphorylation of protein kinase B (to yield p-AKT). Moreover, the IGF-1R ECD from LP increased cell differentiation and the expression of myogenic determination factor (MyoD). CONCLUSION: Our data indicated that the IGF-1R ECD haplotypes between pig breeds with different body sizes affect IGF-1R expression, in turn affecting the proliferation and differentiation of skeletal muscle cells by activating downstream signalling pathways.

Engineering magnetic nano-manipulators for boosting cancer immunotherapy.

Cancer immunotherapy has shown promising therapeutic results in the clinic, albeit only in a limited number of cancer types, and its efficacy remains less than satisfactory. Nanoparticle-based approaches have been shown to increase the response to immunotherapies to address this limitation. In particular, magnetic nanoparticles (MNPs) as a powerful manipulator are an appealing option for comprehensively regulating the immune system in vivo due to their unique magnetically responsive properties and high biocompatibility. This review focuses on assessing the potential applications of MNPs in enhancing tumor accumulation of immunotherapeutic agents and immunogenicity, improving immune cell infiltration, and creating an immunotherapy-sensitive environment. We summarize recent progress in the application of MNP-based manipulators to augment the efficacy of immunotherapy, by MNPs and their multiple magnetically responsive effects under different types of external magnetic field. Furthermore, we highlight the mechanisms underlying the promotion of antitumor immunity, including magnetically actuated delivery and controlled release of immunotherapeutic agents, tracking and visualization of immune response in real time, and magnetic regulation of innate/adaptive immune cells. Finally, we consider perspectives and challenges in MNP-based immunotherapy.

Simultaneous Depth Estimation and Surgical Tool Segmentation in Laparoscopic Images.

Surgical instrument segmentation and depth estimation are crucial steps to improve autonomy in robotic surgery. Most recent works treat these problems separately, making the deployment challenging. In this paper, we propose a unified framework for depth estimation and surgical tool segmentation in laparoscopic images. The network has an encoder-decoder architecture and comprises two branches for simultaneously performing depth estimation and segmentation. To train the network end to end, we propose a new multi-task loss function that effectively learns to estimate depth in an unsupervised manner, while requiring only semi-ground truth for surgical tool segmentation. We conducted extensive experiments on different datasets to validate these findings. The results showed that the end-to-end network successfully improved the state-of-the-art for both tasks while reducing the complexity during their deployment.

Recent Progress in Phase Regulation, Functionalization, and Biosensing Applications of Polyphase MoS2.

The disulfide compounds of molybdenum (MoS2 ) are layered van der Waals materials that exhibit a rich array of polymorphic structures. MoS2 can be roughly divided into semiconductive phase and metallic phase according to the difference in electron filling state of the 4d orbital of Mo atom. The two phases show completely different properties, leading to their diverse applications in biosensors. But to some extent, they compensate for each other. This review first introduces the relationship between phase state and the chemical/physical structures and properties of MoS2 . Furthermore, the synthetic methods are summarized and the preparation strategies for metastable phases are highlighted. In addition, examples of electronic and chemical property designs of MoS2 by means of doping and surface modification are outlined. Finally, studies on biosensors based on MoS2 in recent years are presented and classified, and the roles of MoS2 with different phases are highlighted. This review offers references for the selection of materials to construct different types of biosensors based on MoS2 , and provides inspiration for sensing performance enhancement.

Discovering the Secret of Diseases by Incorporated Tear Exosomes Analysis via Rapid-Isolation System: iTEARS.

Nanoscale small extracellular vesicles (sEVs, exosomes) in tears allow us to investigate the multisignatures of diseases. However, the translations of tear sEVs for biomarker discovery and clinical diagnostics are practically limited by low recovery, long processing time, and small sample volume. Here, we report an incorporated tear-exosomes analysis via rapid-isolation system (iTEARS) via nanotechnology to discover the secrets of ocular disorders and systemic diseases. We isolate exosomes rapidly with high yield and purity from a few teardrops (∼10 µL) within 5 min via nanoporous membrane-based resonators for the quantitative detection and biomarker discovery through proteomic and transcriptomic analysis. We have identified 904 proteins, among which 228 proteins are discovered, 426 proteins are detected from exosomes of dry eye disease, and demonstrate CALML5, KRT6A, and S100P for the classification of dry eye disease. We have also investigated 484 miRNAs in tear exosomes and show miR-145-5p, miR-214-3p, miR-218-5p, and miR-9-5p are dysregulated during diabetic retinopathy development. We believe iTEARS can be used for improving molecular diagnostics via tears to identify ocular disorders, systemic diseases, and numerous other neurodegenerative diseases and cancer.

Magnetic hyperthermia induces effective and genuine immunogenic tumor cell death with respect to exogenous heating.

Immunogenic cell death (ICD) can improve the therapeutic effects of cancer immunotherapy by initiating adaptive immune responses. Unlike the exogenous hyperthermia modality in clinics, magnetic hyperthermia (MH) is characterized by an iron oxide nano-agent acting as a heating source and the effects induced by heating acting at the intracellular region. However, the immunological effects of endogenous heating generated during MH and exogenous heating, and the difference in damage-associated molecular pattern (DAMP) emissions correlating with the ICD are unclear; whether MH elicits genuine ICD remains unknown. Herein, we have identified 10 distinct DAMP correlates of ICD induced by intracellular MH, and found that only heat shock proteins 70/90 were expressed after water bath heating (exogenous hyperthermia) in human triple-negative breast cancer (TNBC) MDA-MB-231 cells, murine TNBC 4T1 cells, and surgically resected specimens of ductal breast cancer from patients. In vivo vaccination assays were performed in immunocompetent BALB/c mice. The results demonstrated that MH with endogenous heating could stimulate the genuine ICD on 4T1 cells and achieved optimal therapeutic effects on 4T1 tumors, whereas exogenous heating under the same conditions failed to elicit these effects. These findings with regard to the MH induced genuine ICD with high efficiency are critical for the development of safe and effective therapeutics to amplify the therapeutic responses of cancer immunotherapy.

General Solution to the Preparation of ß-Thiolated/Selenolated Amino Acids Via Visible Light Catalyzed Asymmetric Giese Reaction.

Thiolated/selenolated amino acids are irreplaceable despite their rare abundance in proteins. They play critical roles in regulating the conformation and function of proteins and peptide design as well as bioconjugation. Furthermore, ß-thiolated/selenolated amino acids are important motifs in native chemical ligation-dechalcogenation strategy for protein synthesis. However, a universal method to access enantiopure ß-thiolated/selenolated amino acids has not been reported. Herein, we developed a practical strategy for the preparation of a variety of enantiopure ß-thiolated/selenolated amino acids via photoredox-catalyzed Giese reaction.

Quinoline-Based Photolabile Protection Strategy Facilitates Efficient Protein Assembly.

Native chemical ligation (NCL) provides a powerful solution to assemble proteins with precise chemical features, which enables a detailed investigation of the protein structure-function relationship. As an extension to NCL, the discovery of desulfurization and expressed protein ligation (EPL) techniques has greatly expanded the efficient access to large or challenging protein sequences via chemical ligations. Despite its superior reliability, the NCL-desulfurization protocol requires orthogonal protection strategies to allow selective desulfurization in the presence of native Cys, which is crucial to its synthetic application. In contrast to traditional thiol protecting groups, photolabile protecting groups (PPGs), which are removed upon irradiation, simplify protein assembly and therefore provide minimal perturbation to the peptide scaffold. However, current PPG strategies are mainly limited to nitro-benzyl derivatives, which are incompatible with NCL-desulfurization. Herein, we present for the first time that quinoline-based PPG for cysteine can facilitate various ligation strategies, including iterative NCL and EPL-desulfurization methods. 7-(Piperazin-1-yl)-2-(methyl)quinolinyl (PPZQ) caging of multiple cysteine residues within the protein sequence can be readily introduced via late-stage modification, while the traceless removal of PPZQ is highly efficient via photolysis in an aqueous buffer. In addition, the PPZQ group is compatible with radical desulfurization. The efficiency of this strategy has been highlighted by the synthesis of γ-synuclein and phosphorylated cystatin-S via one-pot iterative ligation and EPL-desulfurization methods. Besides, successful sextuple protection and deprotection of the expressed Interleukin-34 fragment demonstrate the great potential of this strategy in protein caging/uncaging investigations.

PTP-PEST Regulated Membranous/Cytoplasmic Translocation of p120ctn in the Lung Cancer Resistance to Tyrosine Kinase Inhibitor.

Our previous studies indicate that resistance induction using first-generation tyrosine kinase inhibitors (TKIs) in lung cancer is accompanied with p120-catenin (p120ctn) cytoplasmic translocation from the membrane. However, the molecular mechanism underlying p120ctn intracytoplasmic translocation has not yet been reported. We performed immunohistochemistry to detect the correlation of p120ctn distribution with protein tyrosine phosphatase non-receptor type 12 (PTP-PEST) and p120ctn Y335 phosphorylation levels in non-small cell lung cancer (NSCLC) patients. After resistance induction using first-generation TKIs in lung cancer cells, Western blotting and substrate trapping were used to assess PTP-PEST expression and its influence on p120ctn Y335 phosphorylation, as well as the role of p120ctn Y335 phosphorylation on the association of p120ctn with E-cadherin and p120ctn membrane/cytoplasm translocation. In 197 samples collected from NSCLC patients, cytoplasmic p120ctn and enhanced p120ctn Y335 phosphorylation were associated with decreased PTP-PEST. After resistance induction using gefitinib, decreased PTP-PEST expression was accompanied by enhanced phosphorylation of p120ctn Y335 and p120ctn translocated to the cytoplasm. In gefitinib-resistant cells, PTP-PEST overexpression restrained p120ctn Y335 phosphorylation and restored membrane p120ctn expression. PTP-PEST enhanced the interaction of p120ctn with E-cadherin and elevated p120ctn membrane expression. However, increased p120ctn-Y335F mutant had no effect on p120ctn interaction with E-cadherin and membrane/cytoplasm translocation compared with the control group. In conclusion, resistance to first-generation TKIs inhibited PTP-PEST expression, which promoted p120ctn-Y335 phosphorylation and reduced the interaction of p120ctn with E-cadherin, resulting in p120ctn cytoplasmic translocation.

Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine.

Although serine metabolism plays a crucial role in the proliferation and survival of tumor cells, how it supports tumor cell migration remains poorly understood. Phosphoglycerate dehydrogenase (PHGDH) catalyzes the oxidation of 3-phosphoglycerate to 3-phosphonooxypyruvate, the first committed step in de novo serine biosynthesis. Here we show that PHGDH was monoubiquitinated by cullin 4A-based E3 ligase complex at lysine 146 in colorectal cancer (CRC) cells, which enhanced PHGDH activity by recruiting a chaperone protein, DnaJ homolog subfamily A member 1, to promote its tetrameric formation, thereby increasing the levels of serine, glycine, and S-adenosylmethionine (SAM). Increased levels of SAM upregulated the expression of cell adhesion genes (laminin subunit gamma 2 and cysteine rich angiogenic inducer 61) by initiating SET domain containing 1A-mediated trimethylation of histone H3K4, thereby promoting tumor cell migration and CRC metastasis. Intriguingly, SAM levels in tumors or blood samples correlated with the metastatic recurrence of patients with CRC. Our finding not only reveals a potentially new role and mechanism of SAM-promoted tumor metastasis but also demonstrates a regulatory mechanism of PHGDH activity by monoubiquitination.