Oncogenesis最新文献

The pentose phosphate pathway (PPP) supplies abundant reducing equivalents and biosynthetic precursors to support the rapid proliferation of tumor cells. An increased PPP flux is a hallmark of metabolic reprogramming in tumors. Although nuclear factor of activated T-cells c1 (NFATc1) promotes oncogenesis in various cancers, its role in metabolic reprogramming remains unclear. Here, we demonstrate that NFATc1 enhances NAD kinase (NADK) expression, elevating intracellular NADP⁺ levels to activate the PPP, thereby boosting proliferation. Furthermore, NFATc1 binds to both the p1 and p2 promoters of MDM2, sustaining its expression, thereby promoting metabolic reprogramming and accelerating cell cycle progression. Finally, we demonstrated that NFATc1 inhibitors suppress colorectal cancer (CRC) growth by targeting the NFATc1/NADK and NFATc1/MDM2 axis and synergize with oxaliplatin. In summary, our findings reveal that targeting NFATc1 simultaneously restricts biosynthetic precursors and impairs cell cycle progression in CRC, suggesting that NFATc1 inhibition is a promising therapeutic strategy.

BRCA1, a well-known tumor suppressor, maintains genomic integrity by facilitating homologous recombination (HR) repair and protecting DNA replication forks. However, its roles beyond DNA repair and replication remain largely unexplored. Here, we demonstrate that BRCA1 interacts with the RNA-binding protein PARP13 in the cytoplasm of ovarian cancer cells, with DNA damage enhancing this interaction via DNA-PK. Notably, BRCA1/PARP13 association is essential for cell survival but does not influence DNA repair efficacy following DNA damage. Mechanistically, PARP13 binds and destabilizes the mRNA of the endoplasmic reticulum (ER) membrane protein SEC61G. Upon DNA damage, BRCA1 disrupts PARP13-mediated SEC61G mRNA decay, leading to SEC61G upregulation. Elevated SEC61G levels cause calcium leakage from the ER into the cytosol, activating the pro-survival kinase Akt. These findings identify the BRCA1-PARP13-SEC61G axis as a non-canonical DNA damage response (DDR) pathway and highlight mRNA stability and ER calcium signaling as potential therapeutic targets to overcome chemoresistance. The schematic illustrates the mechanism by which non-canonical BRCA1 promotes cell survival through regulating PARP13-mediated SEC61G mRNA decay. Under DNA damage-free conditions (left panel), SEC61G maintains cellular calcium homeostasis between the endoplasmic reticulum and cytosol to support normal physiological functions. Upon DNA damage induction (right panel), enhanced interaction between BRCA1 and PARP13 attenuates the mRNA degradation activity of PARP13 toward SEC61G, leading to upregulated SEC61G protein expression. The aberrant accumulation of SEC61G triggers endoplasmic reticulum calcium leakage, which subsequently activates the AKT signaling pathway to enhance cell survival capacity.

Multiple myeloma (MM) is an incurable malignancy of plasma cells, with over 35,000 new cases diagnosed annually in the United States. Despite an expanding arsenal of approved therapies, nearly all patients relapse, and mechanisms underlying disease progression remain poorly understood. In particular, the role of long non-coding RNAs (lncRNAs) in MM progression and treatment response is largely unexplored. To address this gap, we performed transcriptome sequencing of newly diagnosed MM (NDMM) patient samples and compared individuals with short progression-free survival (PFS; <24 months) to those with prolonged PFS (>24 months) following standard first-line therapy. We identified 157 lncRNAs upregulated in patients with short PFS, and prioritized the most significantly upregulated transcript, LINC01432, for functional characterization. CRISPR-mediated knockdown of LINC01432 expression results in upregulation of genes associated with interferon-α/γ responses and increases apoptosis. Targeting LINC01432 with locked nucleic acid antisense oligonucleotides also induces apoptosis, which can be rescued by LINC01432 overexpression. Mechanistically, we discovered that LINC01432 binds the RNA-binding protein CELF2 directly. Transcriptomic analysis following depletion of either LINC01432 or CELF2 revealed 108 overlapping target genes, indicating that this lncRNA-protein complex regulates transcriptional programs governing immune activation, stress response, and cell survival. In summary, this study identified lncRNAs associated with NDMM and characterized LINC01432 as a critical regulator of MM cell survival, acting in complex with CELF2 to repress pro-apoptotic and immune response pathways. These findings highlight LINC01432 as a potential therapeutic target for overcoming resistance in MM.

Recent studies have identified glycosylated RNAs (glycoRNAs) as a novel class of biomolecules potentially involved in cancers and immunological diseases. However, their presence and functional roles in glioma remain unexplored. GlycoRNAs were extracted from glioma cells and detected using Ac4ManNAz labeling and Northern blot. Small RNA deep sequencing and qRT-PCR were employed to determine RNA types and content. A sequence-specific RNA-capture magnetic bead system was developed to enrich specific glycoRNAs, such as U2 and U4. Glycan components were analyzed using liquid chromatography-mass spectrometry. CCK-8, adhesion, ki67, TUNEL staining assays were used to evaluate cell viability, adhesion, proliferation and apoptosis. Glioma cells were found to be rich in glycoRNAs, predominantly small RNAs, with U2 and U4 being particularly abundant. These glycoRNAs primarily contained fucosylated and sialylated complex glycans. The depletion of cell-surface glycoRNAs at the observed time point significantly inhibited glioma cell viability and proliferation, without altering cell adhesion or apoptosis levels. This study underscored the significant role of glycoRNAs in glioma proliferation and provided a foundation for further research into their potential as novel biomarkers and therapeutic targets for glioma. Glioma cells U87 and LN229 showed significant enrichment in glycoRNAs, predominantly small RNAs, with U2 and U4 being particularly abundant and specific. Furthermore, these glycoRNAs were found to be modified by multiple glycans, primarily complex, fucosylated, and sialylated structures.

Tumor recurrence is frequently attributed to drug-tolerant cancer cells. We previously demonstrated that downregulation of the Pregnane X Receptor (PXR, NR1I2) reduces chemoresistance and prevents colorectal cancer recurrence in xenograft mouse models. However, there is currently a lack of clinically-suitable PXR antagonists. In this study, we report the design and synthesis of a novel PXR agonist-based PROTAC (JMV7048) which promotes polyubiquitination and degradation of the human PXR protein via E3 CRBN ubiquitin ligase and 26S proteasome pathways. JMV7048 selectively degrades PXR in colon carcinoma, hepatoma, and pancreatic cancer cell lines, with no impact on primary human hepatocytes. Notably, JMV7048 reduces PXR protein expression in drug-tolerant colon cancer cells, sensitizing them to chemotherapy and significantly delaying cancer relapse in xenografted nude mice. These findings suggest that PXR-targeting PROTACs may serve as novel therapeutic agents to enhance the sensitivity of chemo-resistant cancer cells to chemotherapy.

The majority of life-threatening cancers arise from epithelial tissues. These epithelial cancers include cutaneous squamous cell carcinoma (cSCC), the second-most common cancer. cSCC is highly invasive and accounts for an estimated 15,000 deaths each year. We identified SRCAP, a chromatin remodeler that regulates the chromatin occupancy of the histone H2A variant H2A.Z, as a frequently mutated gene in cSCC. Analysis of cSCC mutations in epithelial cancers identified a hotspot truncating mutation in SRCAP, which removes 42% of the protein sequences after amino acid 1879. While SRCAP mutations have been previously connected to the pathogenesis of Floating-Harbor syndrome (FHS), these typically occur downstream, with a hotspot mutation leading to protein truncation after amino acid 2444. We found that expressing the SRCAP-1879 truncation in an HRas-CDK4-driven cSCC model was sufficient to increase proliferation, impair terminal differentiation, and accelerate invasion. Mechanistically, the expression of SRCAP-1879 in primary human keratinocytes was sufficient to dysregulate genes crucial for carcinogenesis (e.g., proliferation, differentiation, and motility) without altering H2A.Z occupancy. In particular, the expression of SRCAP-1879 truncation led to strong induction of the matrix metalloproteinase MMP9 expression level, accompanied by increased keratinocyte cell motility, which was sensitive to matrix metalloprotease inhibition. In contrast, the expression of the SRCAP-FHS truncation did not increase but instead reduced cell motility as well as the expression of MMP9. Taken together, our findings identify a previously under-characterized role of the SRCAP-1879 truncating mutation in promoting multiple aspects of epithelial cancer progression, including invasion, distinct from the well-recognized roles of SRCAP mutations in FHS pathogenesis.

Glucose metabolic reprogramming serves as a regulatory mechanism to support tumor growth. Here, we identified that BRG1, a subunit of the SWI/SNF chromatin remodeling complex encoded by SMARCA4, can inhibit the glycolysis and proliferation of non-small cell lung cancer (NSCLC) cells. Mechanistically, BRG1 promotes the interaction between SHP1 and PKM2, which affects the subcellular localization and pyruvate kinase activity of PKM2 by reducing its phosphorylation at tyrosine 105 and facilitating PKM2 tetramer formation. Thus, we explored a novel biological function of BRG1 in NSCLC, elucidated the impact of BRG1 on glucose metabolism, and provided insights for clinical strategies targeting tumors with this genetic mutation.

Antipsychotic drugs have been shown to suppress tumor growth and induce cell death, but their clinical application remains limited. Pimozide, an FDA-approved antipsychotic, holds significant potential for cancer treatment. However, the mechanisms underlying tumor cell responses to Pimozide remain unclear. In this study, we identify a critical role for peroxisomes in mediating tumor cell resistance to Pimozide. Our findings demonstrate that Pimozide increases peroxisome numbers and that peroxisomal deficiency significantly enhances Pimozide-induced cell death. We show that peroxisomes mitigate Pimozide-induced apoptosis primarily through fatty acid oxidation and ether lipid synthesis, rather than reactive oxygen species (ROS) metabolism. Moreover, Pimozide treatment upregulates peroxisomal lipid-metabolizing enzymes in tumor cells. As key metabolic hubs interconnected with mitochondrial metabolism, peroxisomes support energy homeostasis, thereby preventing Pimozide-induced cell death. These findings underscore the importance of peroxisomes in maintaining mitochondrial morphology and cellular energy homeostasis, offering novel insights into the potential therapeutic applications of Pimozide in cancer treatment.

Survival rates for patients with late-stage colorectal cancer (CRC) remain low due to limited efficacy of current therapeutic regimens. To overcome these challenges, novel drug targets are urgently needed. Macrophage migration inhibitory factor (MIF), an upstream immunoregulatory cytokine, has emerged as a potential target due to its multifaceted role in cancer pathogenesis. During tumorigenesis, MIF protein levels are often elevated in tumor cells through chaperone-mediated stabilization. Although several in vivo studies have implicated MIF in tumor initiation and progression, its role in sustaining established tumors, particularly when derived from epithelial tumor cells, remained unclear. Using a constitutive Mif knockout mouse model, we previously demonstrated that MIF is required for CRC development. Now, we expanded our experimental CRC model towards a more therapeutic rationale. We hypothesized that epithelial-derived MIF is essential for tumor maintenance and might serve as a possible cancer drug target. Therefore, we depleted epithelial MIF during late-stage CRC tumorigenesis in two genetically-engineered and chemically-induced murine CRC models. Our proof-of-principle study reveals that Mif depletion in epithelial tumor cells attenuates cancer maintenance in both CRC models, coinciding with reduced macrophage recruitment and angiogenesis. Our data highlight the potential utility of targeting MIF in CRC patients for therapeutic benefit.