ArticleOncogene2023
HDAC6-G3BP2 promotes lysosomal-TSC2 and suppresses mTORC1 under ETV4 targeting-induced low-lactate stress in non-small cell lung cancer.
Article in Oncogene, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 24 citations in OpenAlex.
- The neuroprotective effect of Cucurbitacin B against Aβ and tau toxicities requires functional HDAC6 and stress granule pathways.Biogerontology · 2026Article
- Lactate-driven pyrimidine synthesis promotes ferroptosis resistance in hepatocellular carcinoma.Molecular biomedicine · 2026Article
- An Analysis of G3BP2 in Non-Small Cell Lung Cancer.Cancers · 2026Article
- Research Progress on the Biological Function, Disease-Driving Mechanism and Clinical Targeting Strategies of G3BP2.Molecules (Basel, Switzerland) · 2026Review
- Research progress of OTUD7B: from structural function and disease mechanisms to clinical translation.Frontiers in immunology · 2026Review
- The role of OTUD1-mediated deubiquitination in disease pathogenesis: from molecular mechanisms to clinical translation.Frontiers in immunology · 2026Review
- Deubiquitination of ETV4 by USP7 Promotes NSCLC Tumorigenesis via MAPK7 Activation.Human mutation · 2026Article
- RNA-binding protein RBM47 in health and disease: molecular mechanisms, preclinical evidence, and translational challenges.Frontiers in immunology · 2026Review
- Targeting the deubiquitinase USP28 in cancer: navigating context-dependent mechanisms and therapeutic resistance.Frontiers in immunology · 2026Review
- Biomolecular condensates in lung cancer: from molecular mechanisms to therapeutic targeting.Cell death discovery · 2025Review
- Triclabendazole inhibits PKM2 nuclear localization and glycolysis by enhancing HDAC6-mediated deacetylation in lung cancer.Journal of translational medicine · 2025Article
- Topoisomerase I Inhibition in ETV4-overexpressed Non-Small Cell Lung Cancer Promotes Replication and Transcription Mediated R-Loop Accumulation and DNA Damage.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Multi-Omics Integration of Lactylation- and PANoptosis-Based Signatures in Lung Adenocarcinoma: Prognostic Stratification and Immune Response.International journal of molecular sciences · 2025Article
- Potential role of lactylation in intrinsic immune pathways in lung cancer.Frontiers in pharmacology · 2025Review
- ETV4‑mediated transcriptional activation of SLC12A5 exacerbates ferroptosis resistance and glucose metabolism reprogramming in breast cancer cells.Molecular medicine reports · 2024Article
- Stress granules play a critical role in hexavalent chromium-induced malignancy in a G3BP1 dependent manner.Environmental pollution (Barking, Essex : 1987) · 2024Article
- Review
- TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitors.Cell & bioscience · 2024Article
- The miR-669a-5p/G3BP/HDAC6/AKAP12 Axis Regulates Primary Cilia Length.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TSC-mTORC1 inhibition-mediated translational reprogramming is a major adaptation mechanism upon many stresses, such as low-oxygen, -ATP, and -amino acids. But how cancer cells hijack the adaptive pathway to survive under low-lactate stress when targeting glycolysis-related signaling remains uncertain. ETV4 is an oncogenic transcription factor frequently dysregulated in human cancer. We previously found that ETV4 is associated with tumor progression and poor prognosis in non-small cell lung cancer (NSCLC). In this study, we report that ETV4 controls HK1 expression and glycolysis-lactate production to activate mTORC1 by relieving TSC2 repression of Rheb in NSCLC cells. Targeting ETV4-induced low-lactate stress is an important input for TSC2 to inhibit mTORC1 and global protein synthesis, while the core stress granule components G3BP2 and HDAC6 are selectively translated. Mechanistically, G3BP2 recruits lysosomal-TSC2 to suppress mTORC1. HDAC6 deacetylates TSC2 to sustain protein stability and associates with G3BP2 to facilitate more recruiting of TSC2 to inactivate mTORC1. In addition, the microtubule retrograde transport activity of HDAC6 drives the aggregate-like perinuclear-mTOR distribution paralleled by lower mTORC1 activity under stress. Thus, HDAC6-G3BP2 is the key complex that promotes lysosomal-TSC2 and suppresses mTORC1 when targeting ETV4, which might represent a critical adaptive mechanism for cell survival under low-lactate challenges.
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