Biology subjects

Wei, G.-H.

Publications and source records attributed to Wei, G.-H..

10 recordsLinked to original sources

bioRxiv2026

β4-integrins safeguard nuclear mechanics to suppress prostate cancer progression

Prostate cancer (PCa) progression is accompanied by profound alterations in cell-extracellular matrix (ECM) adhesion, nuclear architecture and mechanical adaptability, yet the molecular mechanisms linking these processes remain poorly understood. Hemidesmosomes (HDs), formed by 6{beta}4-integrins, anchor epithelial cells to the basement membrane and couple extracellular forces to the intermediate filament (IF) cytoskeleton. Here, we identify a previously unrecognized tumor-suppressive function of {beta}4-integrins in preserving nuclear integrity in prostate epithelial cells. Loss of {beta}4-integrins disrupted the cytokeratin-5 network and its coupling to the nucleus, leading to nuclear softening, lamin remodeling, reduced heterochromatin content and enhanced confined migration. Unexpectedly, proximity-labeling proteomics revealed that {beta}4-integrins engage nuclear pore complex (NPC) components in an 6-independent manner, particularly upon HD disassembly. Selected interactions were validated using proximity ligation and co-immunoprecipitation assays. {beta}4-integrin loss was associated with enlarged nuclear pores and aberrant nucleocytoplasmic transport, including nuclear accumulation of YAP1. Consistent with these findings, reduced {beta}4-integrin expression in a large PCa tissue cohort correlated with altered nuclear morphology, adverse clinicopathological features, metastatic progression, and poor patient survival. Collectively, our study establishes {beta}4-integrins as a critical molecular link between cell-ECM adhesion, nuclear mechanics and genome integrity.

cancer biology↗

bioRxiv2026

A phosphorylation switch in PAGE4 drives MED12-mutant fibroid pathogenesis

Recurrent somatic mutations in MED12, found in [~]70% of uterine leiomyomas (ULs), define the dominant molecular subtype of these highly prevalent tumors, yet the downstream effector mechanisms remain poorly understood. Using an integrated multi-omics workflow, encompassing discovery-phase DDA proteomics of matched leiomyoma-myometrium pairs, validation-phase DIA proteomics across genetically stratified cohorts (MED12 p.G44D, RAD51B-HMGA2, IRS4/FH subtypes), phosphoproteomics, immunohistochemistry, and AP-MS interactomics, we identify prostate-associated gene 4 (PAGE4) as a central effector of MED12-mutant UL pathogenesis. PAGE4 emerged as one of the most significantly upregulated proteins in MED12-mutant ULs and harbored the highest-occupancy hyperphosphorylation sites (T51, T85) in the tumor phosphoproteome, a pattern confirmed by immunohistochemistry and orthogonal phosphoproteomics. Kinase-substrate enrichment nominated HIPK2 as the primary upstream kinase, with supporting evidence from the broader CMGC family. Subsequent analysis revealed that phosphorylation acts as a molecular switch, fundamentally restructuring the PAGE4 interactome to favor the Mediator complex and RNA Pol II transcriptional machinery. This rewiring was functionally validated by ChIP-seq and luciferase reporter assays, which demonstrated corresponding shifts in transcription factor occupancy and downstream pathway activity. Collectively, these data establish phospho-PAGE4 as a critical mechanistic node downstream of MED12 mutation, expand PAGE4 biology from prostate cancer to female reproductive tumors, and nominate it as a mechanistic biomarker and candidate therapeutic vulnerability in the most prevalent molecular subtype of uterine leiomyomas.

systems biology↗

bioRxiv2025

Machine learning-based definition of cellular senescence reveals pro-senescence potential implication in lung adenocarcinoma

Despite growing evidence implicating cellular senescence in tumor progression, methodological challenges in objectively quantifying senescent cell burden across cancer types continue to limit mechanistic studies and clinical translation. To address this, we developed the Predictive Cellular Senescence Model (PreCSenM), a machine learning-based tool that assigns a CS score by integrating senescence-associated features across 888 samples. Benchmarking analyses confirmed that PreCSenM markedly outperforms existing methodologies in reliably predicting senescent states within both normal and cancerous transcriptomic datasets. In lung adenocarcinoma (LUAD), PreCSenM identified the CS score as a robust predictor of clinical outcomes. Multi-omics analyses further revealed that lower CS levels correlate with decreased genomic stability and enhanced immune responses, aligning with clinical observations. Notably, drug discovery using PreCSenM identified histone deacetylase inhibitors (HDACis) as potent inducers of CS in LUAD. Transcriptional and epigenetic profiling of HDACi-treated cells pinpointed FOSB as a core transcription factor driving CS, and FOSB knockdown blocked HDACi-induced senescence. Overall, our study establishes PreCSenM as a multidimensional senescence quantification tool, bridging computational prediction with clinical relevance and mechanistic validation to enable senescence-directed therapies in precision oncology.

bioinformatics↗

bioRxiv2024

RFX6 at locus 6q22 confers metastasis and drug resistance in prostate cancer

Genetic and nonmutational epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and contributing to tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with recent multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. We uncover that rs339331 resides at a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy under androgen signaling. We establish that RFX6 is an AR-regulated gene, intricately linked with rs339331, exhibiting synergistic prognostic value for PCa recurrence and metastasis. Through comprehensive in vitro and in vivo studies, we establish the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates transcription factor HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) process and modulating the TGF{beta}/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores responsiveness of enzalutamide-resistant PCa cells and tumors to treatment. Our study highlights an interplay of disrupted genetic and epigenetic mechanisms converging on prostate lineage AR signaling, resulting in abnormal expression of RFX6 conferring PCa pathogenesis and enzalutamide resistance.

cancer biology↗

bioRxiv2023

Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity

ZMYND11 encodes an epigenetic reader of histone methylation, functioning as a transcriptional corepressor. However, whether and how ZMYND11 contributes to cancer progression and therapy remains unclear. Here we report that ZMYND11 downregulation is prevalent in cancers and profoundly correlates with adverse prostate cancer patient outcomes. Depletion of ZMYND11 promotes tumor cell growth, migration and invasion in vitro as well as tumor formation and metastasis in vivo. Mechanistically, we find that ZMYND11 exhibits tumor suppressive roles through recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby squeezing HNRNPA1 in nucleus and inhibiting the formation of stress granules in cytoplasm. Furthermore, ZMYND11 antagonizes HNRNPA1-driven high PKM2/PKM1 ratio and counteracts PKM2-induced aggressive tumor phenotype. Remarkably, ZMYND11 recognition of HNRNPA1 could be disrupted by pharmaceutical inhibition of arginine methyltransferase PRMT5 while ZMYND11 low-expressing tumors are sensitive to the treatment of PRMT5 inhibitors. Collectively, our study unravels a novel and noncanonical function of ZMYND11 as the nonhistone methyl reader and discovers a mechanism for the requirement of arginine-methylation-mediated ZMYND11-HNRNPA1 association to restrict tumor progression and offers cancer therapeutic targets and potential biomarkers.

cancer biology↗

bioRxiv2023

TEAD1 regulates ITGA1 and ITGA2 to control prostate cancer progression

The extracellular matrix (ECM) undergoes significant changes during prostate cancer (PCa) progression and actively regulates PCa growth and invasion. Here, we performed a meta-analysis of PCa cohorts and found that downregulation or loss of ITGA1 and ITGA2 integrin genes was associated with tumor progression to metastasis and poor prognosis in PCa patients. Genomic deletion of both 1- and 2-integrins activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT was induced by enhanced secretion and subsequent activation of autocrine TGF{beta}1 and nuclear targeting of YAP1. Our unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of 2- and 2-integrins in vitro and in vivo. Notably, clinical data analysis revealed that TEAD1 downregulation or loss was associated with aggressive PCa and could synergize with ITGA1 and ITGA2 expression to impact PCa prognosis and progression. Altogether, our results demonstrate that loss of 1- and 2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGF{beta}1-driven EMT.

cancer biology↗

bioRxiv2023

Combined CRISPR and proteomics screening reveal a cohesin-CTCF-bound allele contributing to increased expression of RUVBL1 and prostate cancer progression

Genome-wide association studies along with expression quantitative trait loci (eQTL) mapping have identified hundreds of single nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9133 guide RNAs (gRNAs) to target 2,166 candidate SNP sites implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in the screening (FDR<0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (pvalue=1.2E-16 and 3.2E-7). Subsequent eQTL analysis revealed that the G allele is associated with increased RUVBL1 expression in multiple datasets. Further CRISPRi and xCas9 base editing proved the rs60464856 G allele leading to an elevated RUVBL1 expression. Furthermore, SILAC-based proteomic analysis demonstrated allelic binding of cohesin subunits at the rs60464856 region, where HiC dataset showed consistent chromatin interactions in prostate cell lines. RUVBL1 depletion inhibited PCa cell proliferation and tumor growth in xenograft mouse model. Gene set enrichment analysis suggested an association of RUVBL1 expression with cell-cycle-related pathways. An increased expression of RUVBL1 and activations of cell-cycle pathways were correlated with poor PCa survival in TCGA datasets. Together, our CRISPRi screening prioritized about one hundred regulatory SNPs essential for prostate cell proliferation. In combination with proteomics and functional studies, we characterized the mechanistic role of rs60464856 and RUVBL1 in PCa progression.

genetics↗

bioRxiv2021

Disassembly of hemidesmosomes promotes tumorigenesis in PTEN-negative prostate cancer by targeting plectin into focal adhesions

Loss of 6{beta}4-dependent hemidesmosomes has been observed during prostate cancer progression. However, the significance and underlying mechanisms by which aberrant hemidesmosome assembly may modulate tumorigenesis remain elusive. Using an extensive CRISPR/Cas9-mediated genetic engineering approaches in different prostate cancer cell lines combined with in vivo tumorigenesis studies in mice, bone marrow-on-chip assays and bioinformatics, as well as histological analysis of prostate cancer patient cohorts, we demonstrated that simultaneous loss of PTEN and hemidesmosomes induced several tumorigenic properties including proliferation, migration, resistance to anoikis, apoptosis, and drug treatment in vitro, and increased metastatic capacity in vivo. Our studies showed that these effects were driven by activation of EGFR/PI3K/Akt and FAK/Src-pathways and were abolished by plectin downregulation. Therefore, dual loss of PTEN and hemidesmosomes may have diagnostic value helping to stratify prostate cancer patients with high risk for development of aggressive disease and highlight plectin as a potential therapeutic target in prostate cancer.

cancer biology↗

bioRxiv2021

Extensive germline-somatic interplay drives prostate cancer through HNF1B co-option of TMPRSS2-ERG

Genome-wide association studies have identified 270 loci conferring risk for prostate cancer (PCa), yet the underlying biology and clinical impact remain to be investigated. Here we observe an enrichment of transcription factor genes including HNF1B within PCa risk-associated regions. While focused on the 17q12/HNF1B locus, we find a strong eQTL for HNF1B and multiple potential causal variants involved in the regulation of HNF1B expression in PCa. An unbiased genome-wide co-expression analysis reveals PCa-specific somatic TMPRSS2-ERG fusion as a transcriptional mediator of this locus and the HNF1B eQTL signal is ERG fusion status dependent. We investigate the role of HNF1B and find its involvement in several pathways related to cell cycle progression and PCa severity. Furthermore, HNF1B interacts with TMPRSS2-ERG to co-occupy large proportion of genomic regions with a remarkable enrichment of additional PCa risk alleles. We finally show that HNF1B co-opts ERG fusion to mediate mechanistic and biological effects of the PCa risk-associated locus 17p13.3/VPS53/FAM57A/GEMIN4. Taken together, we report an extensive germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations underpinning PCa risk association and progression.

cancer biology↗

bioRxiv2018

Hydrogen sulfide promotes nodulation and nitrogen fixation in soybean-rhizobia symbiotic system

The rhizobium-legume symbiotic system is crucial for nitrogen cycle balance in agriculture. Hydrogen sulfide (H2S), a gaseous signaling molecule, may regulate various physiological processes in plants. However, whether H2S has regulatory effect in this symbiotic system remains unknown. Herein, we investigated the possible role of H2S in the symbiosis between soybean (Glycine max) and rhizobium (Sinorhizobium fredii). Our results demonstrated that exogenous H2S donor (sodium hydrosulfide, NaHS) treatment promoted soybean growth, nodulation and nitrogenase (Nase) activity. Western blotting analysis revealed that the abundance of nitrogenase component nifH was increased by NaHS treatment in nodules. Quantitative real-time PCR data showed that NaHS treatment up-regulated the expressions of symbiosis-related genes nodC and nodD of S. fredii. Besides, expression of soybean nodulation marker genes including early nodulin 40 (GmENOD40), ERF required for nodulation (GmERN), nodulation signaling pathway2b (GmNSP2b) and nodulation inception genes (GmNIN1a, GmNIN2a and GmNIN2b) were up-regulated. Moreover, the expressions of glutamate synthase (GmGS), nitrite reductase (GmNiR), ammonia transporter (GmSAT1), and nifH involved in nitrogen metabolism were up-regulated in NaHS-treated soybean roots and nodules. Together, our results suggested that H2S may act as a positive signaling molecule in soybean-rhizobia symbiotic system and enhance their nitrogen fixation ability.\n\nHighlightWe demonstrated for the first time that H2S as a signaling molecule may promote the establishment of symbiotic relationship and nitrogen fixation ability in the soybean-rhizobia symbiotic system.

plant biology↗