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L-2-hydroxyglutarate modulates ferroptosis through Nrf2/Slc7a11 and Atf4/Chac1 axes in hepatocellular carcinoma

ABSTRACT: L-2-hydroxyglutarate modulates ferroptosis through Nrf2/Slc7a11 and Atf4/Chac1 axes in hepatocellular carcinoma

PROVIDER: PRJNA1289662 | ENA |

REPOSITORIES: ENA

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L-2-hydroxyglutarate modulates ferroptosis through Nrf2/Slc7a11 and Atf4/Chac1 axes in hepatocellular carcinoma

Project description:Liver tumors undergo profound metabolic reprogramming to support survival, proliferation, and metastasis. Through a metabolic library screen combined with network-level integration of transcriptomic and metabolomic data, we identified a regulatory role of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and its substrate, L-2-hydroxyglutarate (L2HG), on ferroptosis in hepatocellular carcinoma (HCC), which exhibits a metabolic environment prone to L2HG accumulation. Mechanistically, L2HG was found to promote chromatin accessibility at ferroptosis-related gene loci. Specifically, L2HG conferred protection against ferroptosis by enhancing cystine uptake via NRF2/SLC7A11 activation, while concurrently sensitizing cells to ferroptosis through glutathione degradation via ATF4/CHAC1 induction. The ferroptosis-protective effect of L2HG was dependent on NRF2, the ablation of which restored near-normal metabolic profiles in a spontaneous liver tumor mouse model. These findings suggest that the metabolically accumulated L2HG plays a dual role in modulating both ferroptosis resistance and sensitivity, thereby influencing liver tumorigenesis. Targeting these metabolic axes may provide novel strategies for ferroptosis-based antitumor therapies.

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ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to suppress stress-related ferroptosis

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The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis (Tunicamycin)

Project description:In response to a variety of upstream growth and oncogenic signals, the mechanistic target of rapamycin complex 1 (mTORC1) promotes anabolic metabolism, in part, through activation of downstream transcription factors. The transcription factor activating transcription factor 4 (ATF4) has been previously shown to function downstream of mTORC1 signaling to promote de novo purine synthesis and this activation of ATF4 can occur independently of the canonical activation of ATF4 through the integrated stress response (ISR). Here, we show that ATF4 activation through mTORC1 signaling drives a specific transcriptional program through ATF4 which is comprised of only a subset of genes involved in the broader cellular stress response. We find genes involved in amino acid uptake, biosynthesis, and charging by tRNA synthetases display transcriptional changes downstream of both mTORC1 and ATF4. We discovered that ATF4 activation contributes to the mTORC1-stimulated increase in protein synthesis, highlighting the importance of these transcriptional changes. Additionally, we observe regulation of the cystine transporter SLC7A11 by ATF4. We show that SLC7A11 is important for cell survival and is one mechanism by which cells with active mTORC1 signaling produce glutathione. Thus, ATF4 downstream of mTORC1 signaling regulates protein and glutathione synthesis.

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Effects of overexpression of GFP-TDP-43, GFP-TDP-43(86-414) or GFP in human H4 cells, in the presence or absence of the EIF2B activator DNL343.

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