N6-methyladenosine (m6A) represents the most abundant mRNA modification, yet its role in natural killer (NK) cell development remains incompletely understood. Here we demonstrate that the m6A methyltransferase METTL14 plays an indispensable, stage-specific role in early NK cell development. Mettl14 deficiency at the progenitor stage caused severe NK cell lymphopenia by disrupting the NK progenitor to immature NK cell transition. Paradoxically, residual Mettl14-null NK cells exhibited a hypermetabolic state characterized by mTORC1 hyperactivation and enhanced mitochondrial function, which drove both hyperproliferation and activation-induced cell death via p53 and apoptotic pathway activation. Despite developmental defects, these cells demonstrated superior capacity to control melanoma metastasis in vivo. Mechanistically, METTL14 fine-tuned IL-15 responsiveness likely by sustaining SOCS3 expression to restrain JAK-STAT5 signaling. Terminal deletion of Mettl14 produced no phenotype, underscoring its specific requirement during early development. Our findings establish METTL14 as a crucial checkpoint coordinating transcriptional and metabolic programs to ensure NK cell homeostasis.
Thymic epithelial tumors (TETs) are heterogeneous neoplasms. While most early-stage cases are curable after resection, advanced or aggressive subtypes have limited treatment options and poor outcomes. The molecular mechanisms underlying their metabolic reprogramming remain poorly understood. Proline-rich Coiled-coil 2a (PRRC2A), a N6-methyladenosine (m6A) reader protein, is significantly upregulated in TET tissues and is associated with poor clinical outcomes. Multi-omics analyses and molecular experiments revealed that PRRC2A binds to m6A-modified sites within the NCOA4 mRNA, thereby stabilizing NCOA4 transcripts and enhancing its protein expression. Elevated NCOA4 interacts with PKM2, a rate-limiting glycolytic enzyme, resulting in increased glycolysis and promoting TETs progression. In vivo experiments showed that inhibition of PRRC2A suppressed tumor growth and metastasis in TETs, while combined treatment with the PKM2 inhibitor C599 and PRRC2A knockdown produced enhanced antitumor effects. These findings provide novel insights into the glycolytic metabolic regulation of TETs and suggest that the PRRC2A-NCOA4-PKM2 axis represents a promising therapeutic target.
Genetic inactivation of alpha-galactosidase A (GLA) causes Fabry disease, which is characterized by early cutaneous lesions such as angiokeratomas. However, the role of GLA in malignancies like melanoma remains poorly understood. Here, we show that high expression of GLA correlates with tumor development and progression, including in melanoma. GLA overexpression enhances B16 melanoma cell survival and proliferation by activating mTORC1 signaling, whereas GLA deficiency suppresses mTORC1 and enhances lysosome biogenesis through its downstream transcription factor EB (TFEB). Loss of GLA enzymatic activity also impairs autolysosome formation and autophagic flux, thereby disrupting the autophagy-lysosomal pathway. Mechanistically, the GLA precursor is diverted from the secretory pathway and directly interacts with subunits of the GAP activity toward Rags complex 1 (GATOR1) on the lysosomal surface, sensitizing nutrient-sensing signals upstream of mTORC1. Notably, catalytically inactive GLA mutants retain the ability to activate mTORC1 and promote tumor growth, supporting an enzyme-independent oncogenic function of GLA. Together, these findings reveal a GLA-GATOR1-mTOR regulatory axis critical for melanoma development and identify GLA as a potential biomarker for distinguishing benign angiokeratoma from malignant melanoma.
The mammalian target of rapamycin (mTOR) signalling is crucial in promoting tumor growth and metastasis. Yet current mTOR inhibitors face limitations due to resistance and adverse effects. Inhibitors block the cytoplasmic signalling of mTOR, which may induce feedback loops that activate other cell proliferative signalling or reactivates mTOR itself, making it difficult to achieve complete inhibition of mTOR activities. In this study, we identified tubulointerstitial nephritis antigen (TINAG), a kidney-specific extracellular matrix protein, as an extracellular regulator of mTOR. Our data demonstrate that TINAG binds to integrin α3β1 transducing negative signals that suppress mTORC1 activity in tumor and endothelial cells, thereby reducing proliferation, migration, and angiogenesis. In both in vitro and in vivo models, TINAG protein exhibited pronounced inhibition on RCC growth and metastasis in wild-type RCC tumor and a sorafenib-resistant tumor model. Surprisingly, we also found the integrin α3β1 receptor with its canonical ligands did not promote cell growth, on the contrary, integrin α3β1 overexpression inhibited cell growth and migration. More interestingly, TINAG also exhibited an antiangiogenic potential, which functioned as a dual inhibitor on tumor cell and blood vessels simultaneously. Our finding reveals an extracellular mechanism regulating mTORC1 via TINAG-integrin interaction, suggesting TINAG as a novel tumor suppressor and promising dual targeting therapeutic candidate for RCC treatment.
Aberrant DNA damage responses can result in genomic instability, thereby affecting the efficacy of radiotherapy. The transcription factor FOXN3 plays critical roles in cellular growth and proliferation, inflammation, and the response to injury; however, its involvement in lung cancer radioresistance remains unclear. Here, we revealed that reduced expression of FOXN3 was correlated with poor prognosis in lung adenocarcinoma patients and that FOXN3 depletion impaired the DNA damage response, thereby conferring radioresistance in lung cancer. Mechanistically, FOXN3 promoted BRCA1 transcription by binding to the BRCA1 promoter region, thereby increasing DNA damage. Furthermore, the protein kinase RSK2 and E3 ubiquitin ligase β-Trcp collaboratively interacted with FOXN3, facilitating its ubiquitination-mediated degradation via a conserved DSGYAS motif. Importantly, this cooperative degradation of FOXN3 attenuated DNA damage and promoted radioresistance in lung cancer cells. Our study provides a mechanistic foundation for targeting FOXN3-related pathways as a potential strategy to overcome radioresistance in lung cancer.
