Biology subjects

Wang, L.-H.

Publications and source records attributed to Wang, L.-H..

5 recordsLinked to original sources

bioRxiv2024

Host-derived Lactobacillus plantarum alleviates hyperuricemia by improving gut microbial community and hydrolase-mediated degradation of purine nucleosides

AbstractGut microbiota has been considered to be associated with the development of hyperuricemia (HUA) and gout. Some prebiotics from different sources had the potential alleviation function in HUA. However, whether host-derived potential probiotics, like Lactobacillus, from the gut of HUA animals could prevent the development of HUA is still uncertain. In this study, we established a HUA geese model and isolated a Lactobacillus plantarum strain, SQ001, from the cecum of HUA geese. Nucleoside co-culture and metabolomics analyses revealed that L. plantarum SQ001 is involved in the absorption and hydrolysis of nucleosides. Whole genome analysis showed there are four genes related with nucleosides hydrolysis in L. plantarum SQ001. The function of iunH, a nucleoside hydrolase gene, was further confirmed by heterologous expression and knockout assays. Oral administration of L. plantarum SQ001 in HUA geese models upregulated the Lactobacillus abundance and reduced serum uric acid (UA) levels. Likewise, in mouse models, L. plantarum SQ001 increased the L. plantarum abundance and lowered serum UA levels by reducing hepatic UA synthesis protein XO and renal UA reabsorption protein GLUT9 expression, while increasing renal UA excretion protein ABCG2 expression. Our findings demonstrated that host-derived probiotics from geese could alleviate gut microbe dysbiosis and HUA in its host and mouse model. This study provides insights into the potential probiotic role of Lactobacillus plantarum in HUA or gout therapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/606206v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@698e7eorg.highwire.dtl.DTLVardef@a2091org.highwire.dtl.DTLVardef@e0348aorg.highwire.dtl.DTLVardef@19958ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

CD24a knockout transforms the tumor microenvironment from cold to hot by promoting tumor-killing immune cell infiltration in a murine triple-negative breast cancer model

BackgroundCD24 plays a crucial role not only in promoting tumor progression and metastasis but also in modulating macrophage-mediated anti-tumor immunity. However, the impact of tumor CD24 on the immune landscape of the tumor microenvironment (TME) remains poorly explored. Here, we investigated the role of CD24a, murine CD24 gene, in the progression and immune dynamics of the tumor microenvironment (TME) in the 4T1 murine model of triple-negative breast cancer (TNBC). Methods: We employed Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 technology to perform a gene knockout of Cd24a in 4T1 cells. Flow cytometry was utilized to analyze the distribution and number of immune cells, including myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, T cells, and macrophages, within tumors, spleens, and bone marrow. Immunofluorescence (IF) staining was used to detect these immune cells in tumor sections. Additionally, ANDOR Dragonfly High-Speed Confocal was used to perform three-dimensional (3D) mapping of mouse tumors. ResultsOur study showed that knocking out CD24a significantly impeded tumor progression and prolonged mouse survival. Flow cytometry and IF analysis revealed that the loss of CD24a transformed tumor microenvironment from cold to hot by promoting the infiltration of M1 macrophages, cytotoxic CD8+ T cells, and CD49b+ natural killer (NK) cells while reducing the recruitment and expansion of granulocytic myeloid-derived suppressor cells (gMDSCs) in the TME. Additionally, the 3D mapping of TME further validated the "hot state" of CD24a knockout tumors. ConclusionsOur study provides the first evidence that targeting CD24a could effectively reprogram the TME, enhancing its immunogenicity, and transforming immune cold tumors into hot tumors. This strategy may offer a promising therapeutic strategy for enhancing the immune response against poorly immunogenic tumors.

cancer biology↗

bioRxiv2024

The tumor-maintaining function of UTX/KDM6A in DNA replication and the PARP1-dependent repair pathway

Histone H3K27 demethylase UTX (aka KDM6A) is mutated in many human cancers, suggesting its tumor suppressive role during cancer development. However, most tumors still express wild-type UTX/KDM6A and its function is not always linked to tumor suppression. Here, we present evidence of UTX/KDM6As role in sustaining tumor growth, revealing its function in tumor maintenance. We find that UTX/KDM6A sustains tumor cell cycling and survival via regulating DNA replication-associated transcriptional programs in a demethylase-independent manner. UTX/KDM6A can also interact with PARP1 and facilitate its recruitment to DNA lesions. Therefore, UTX/KDM6A depletion disrupts DNA replication and repair pathways, activating ATM-CHK2 and ATR-CHK1 signaling pathways and triggering S and G2/M checkpoints, leading to a pronounced defect in tumor growth. Analysis of human cancer xenograft models further demonstrates that knockdown of UTX/KDM6A by RNA-interference, rather than inhibition of its enzymatic activity via GSK-J4, shows potent anticancer effects. Dual inhibition of UTX/KDM6A and ATR further demonstrates synergistic anticancer activities. Our work highlights UTX/KDM6A as a potential therapeutic target for cancer treatment, especially when combined with ATR inhibition. HighlightsO_LIUTX/KDM6A contributes to tumor maintenance by promoting the growth and survival of tumor cells C_LIO_LITumor cells rely on UTX/KDM6A to maintain DNA replication, cell cycling, and DNA damage repair C_LIO_LIUTX/KDM6A depletion triggers S and G2/M checkpoints via activating ATM-CHK2 and ATR-CHK1 signaling pathways C_LIO_LITargeting UTX/KDM6A may prove to be an innovative strategy for cancer therapy, whether employed independently or in conjunction with ATR inhibitors. C_LI The Paper ExplainedO_ST_ABSProblemC_ST_ABSThe aggressive growth of tumors relies significantly on heightened proliferation rates and genomic instability, which necessitate robust DNA replication machinery and efficient DNA damage repair mechanisms for tumor cell survival and proliferation. UTX/KDM6A, a histone demethylase central to chromatin and epigenetic regulation, is commonly mutated in various human cancers. However, its role as a tumor suppressor or promoter remains unclear across different cancer contexts. This study delves into the potential tumor-maintaining role of UTX/KDM6A in cancer progression and tumorigenesis, establishing the mechanistic foundation for its tumor-promoting function. ResultsWe uncover UTX/KDM6As crucial role in tumor maintenance via its participation in DNA replication and repair pathways. Surprisingly, we find that its histone demethylase activity is dispensable for these functions, implying an alternative role as a scaffold protein. Consequently, our findings suggest that targeting the entire UTX/KDM6A gene or protein, rather than inhibiting its enzymatic activity, holds promise as a therapeutic strategy for tumors dependent on its tumor-maintaining function. ImpactThis study unveils UTX/KDM6As multifaceted role in cancer progression, shedding light on its diverse contributions to tumorigenesis. Our findings suggest promising therapeutic strategies for cancer treatment, highlighting the importance of targeting UTX/KDM6A and its impact on DNA replication and repair pathways. These discoveries set the stage for further exploration of UTX/KDM6A-mediated mechanisms in clinical settings, indicating potential applications in future clinical trials and combination therapy strategies.

cancer biology↗

bioRxiv2023

Hydrogen Sulfide Coordinates Glucose Metabolism Switch through Destabilizing Tetrameric Pyruvate Kinase M2

Cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation toward aerobic glycolysis. Pyruvate kinase M2 (PKM2), which converts phosphoenolpyruvate (PEP) to pyruvate, is considered the rate-limiting enzyme involved in cancer glucose metabolism. By reducing PKM2 enzyme activity, cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes PKM2 tetramer into dimer/monomer, leading to reduced PKM2 enzyme activity and an increase in the activation of nuclear transcriptional genes mediated by dimeric PKM2. Proteomic profiling of endogenous PKM2 reveals the occurrence of sulfhydration at cysteines, notably at cysteine 326. Blocking PKM2 sulfhydration at cysteine 326 through amino acid mutation stabilizes PKM2 tetramer and crystal structure further indicating that the tetramer organization of PKM2C326S is different from the currently known T or R states, revealing PKM2C326S as a newly identified form. The presence of a PKM2C326S mutant in cancer cells effectively rewires glucose metabolism to mitochondrial respiration, resulting in the significant inhibition of tumor growth. Collectively, PKM2 sulfhydration by H2S serves as a glucose metabolic rewiring mechanism in promoting tumorigenesis, and inhibition of PKM2 sulfhydration may be applied as a new therapeutic approach targeting cancer metabolism. One-Sentence SummaryH2S rewires glucose metabolism by destabilizing PKM2 tetramerization majorly through sulfhydration at cysteine 326 HighlightsO_LIH2S enhances PKM2 dissociation from tetramer to dimer to facilitate dimeric PKM2 nuclear translocation. C_LIO_LIH2S modifies PKM2 sulfhydration, notably at cysteine 326. C_LIO_LIThe crystal structure reveals PKM2C326S as a unique tetramer conformation. C_LIO_LIBlockage of PKM2 sulfhydration at C326 rewires cancer glucose metabolism and significantly inhibits tumor growth. C_LI

cancer biology↗

bioRxiv2020

Neurodegeneration induces a developmental RNA processing program by calpain-mediated MBNL2 degradation

The Muscleblind-like (MBNL) protein family plays an important role in regulating developmental RNA processing transition. Loss of MBNL2 function has been implicated in the neurodegeneration of myotonic dystrophy type 1 (DM1). However, the causal mechanism of neurodegeneration-induced MBNL2 loss of function remains elusive. Here, we show that neurodegenerative conditions including NMDAR-mediated excitotoxicity and dysregulated calcium homeostasis triggered nuclear translocation of calpain-2 resulting in MBNL2 degradation and reversion of MBNL2-regulated RNA processing to developmental patterns. The developmental stage featured nucleus-enriched distribution of calpain-2 and low expression of MBNL2. Increased MBNL2 expression during development is required for promoting developmental RNA processing transition and neuronal maturation. Knockdown of calpain-2 expression inhibited neurodegeneration-induced MBNL2 reduction and dysregulated RNA processing. Neurodegenerative disease mouse models including DM1 and Alzheimers disease showed nuclear translocation of calpain-2 associated with MBNL2 degradation and reversion of MBNL2-regulated RNA processing to the developmental pattern. Our results identify a novel regulatory mechanism for MBNL2 downregulation and suggest that reduced MBNL2 expression accompanied by the re-induction of a developmental RNA processing program may be a common feature of neurodegeneration.

neuroscience↗