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HDAC6-G3BP2 promotes lysosomal-TSC2 and suppresses mTORC1 under ETV4 targeting-induced low-lactate stress in non-small cell lung cancer

Oncogene volume 42, pages 1181–1195 (2023)Cite this article

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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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Fig. 1: ETV4 regulates glycolytic enzyme HK1 expression to control aerobic glycolysis in NSCLC cells.
Fig. 2: ETV4-lactate regulates TSC2-Rheb-dependent mTORC1 activation as well as mTOR distribution in NSCLC cells.
Fig. 3: ETV4 knockdown induces low-lactate stress leading to downregulation of total protein synthesis in NSCLC cells.
Fig. 4: ETV4 knockdown-induced low-lactate relieves G3BP2 repression in NSCLC cells.
Fig. 5: G3BP2 inhibits mTORC1 activity through upregulation of TSC2-Rheb interaction in si-ETV4 NSCLC cells.
Fig. 6: HDAC6 induces perinuclear-mTOR distribution and the lower mTORC1 activity in si-ETV4 NSCLC cells.
Fig. 7: HDAC6 deacetylates TSC2, leading to modulation of protein stability and mTORC1 activity.
Fig. 8: HDAC6 associates with G3BP2 to facilitate more recruiting of TSC2 to inactivate mTORC1 in si-ETV4 NSCLC cells.

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Data availability

The Microarray data have been uploaded to the NCBI Gene Expression Omnibus (GEO) database under accession numbers GSE137445. All other data supporting the findings of this study are available from the corresponding author upon reasonable request. The figshare DOI is https://doi.org/10.6084/m9.figshare.21788945.

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Acknowledgements

This work was supported by Grants 81572275 from the National Natural Science Foundation of China, Grants U20A20369 from the National Natural Science Foundation of China, Grants H2020206234 and H2020206374 from the Natural Science Foundation of Hebei province, China, and Grants WZYCZY202003 from Hebei Provincial Department of Science and Technology, China.

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Authors and Affiliations

  1. Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

    Bei Liu, Jiaxi Zhang, Xue Meng, Shelly M. Xie, Fang Liu, Heli Chen, Demin Yao, Minglei Li, Minghui Guo, Haitao Shen, Xianghong Zhang & Lingxiao Xing

  2. Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

    Haitao Shen, Xianghong Zhang & Lingxiao Xing

  3. Department of Pathology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China

    Xianghong Zhang

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Contributions

LX designed the study and wrote the paper. BL developed the method and performed research. JZ, XM, FL, HC, DY, and MG helped to perform the in vitro assays and FCM analysis.. SMX participated in writing and revising the manuscript. ML contributed to the data analysis. HS and XZ reviewed and edited the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Lingxiao Xing.

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Liu, B., Zhang, J., Meng, X. et al. HDAC6-G3BP2 promotes lysosomal-TSC2 and suppresses mTORC1 under ETV4 targeting-induced low-lactate stress in non-small cell lung cancer. Oncogene 42, 1181–1195 (2023). https://doi.org/10.1038/s41388-023-02641-6

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