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TGF-?1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells.

ABSTRACT: System x_c^- contributes to glutathione (GSH) synthesis and protects cells against ferroptosis by importing cystine and exchanging it with glutamate. Transforming growth factor ?1 (TGF-?1) induces redox imbalance; however, its role in system x_c^- regulation remains poorly understood. The present study was the first to show that TGF-?1 repressed the protein and mRNA levels of xCT, a catalytic subunit of system x_c^-, in PLC/PRF/5, Huh7, Huh6, and HepG2 cells with an early TGF-?1 gene signature but not in SNU387, SNU449, SNU475, and SK-Hep1 cells with a late TGF-?1 gene signature. TGF-?1 treatment for 24?h reduced xCT expression in a dose-dependent manner but this TGF-?1-induced repression was blunted by pretreatment with a TGF-?1 receptor inhibitor. TGF-?1-mediated xCT repression was prevented by Smad3, but not Smad2 or Smad4, knockdown, whereas it was enhanced by Smad3 overexpression. TGF-?1 decreased GSH levels in control cells but not xCT-overexpressed cells. Furthermore, TGF-?1 increased reactive oxygen species (ROS) levels in PLC/PRF/5 cells and enhanced tert-butyl hydroperoxide-induced ROS levels in Huh7 cells; these changes were reversed by xCT overexpression. TGF-?1 treatment ultimately induced the ferrostatin-1- and deferoxamine-dependent lipid peroxidation after 2 days and 8 days in PLC/PRF/5 and Huh7 cells but not in SNU475 and SK-Hep1 cells. Pre-treatment of TGF-?1 for 2 days enhanced the reduction of cell viability induced by RSL3, a GSH peroxidase 4 (GPX4) inhibitor, in PLC/PRF/5 and Huh7 cells. In conclusion, TGF-?1 represses xCT expression via Smad3 activation and enhances lipid peroxidation in hepatocellular carcinoma cells with an early TGF-?1 signature, which would benefit from the targeting of GPX4.

SUBMITTER: Kim DH

PROVIDER: S-EPMC7260246 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells.

Kim Do Hyung DH Kim Won Dong WD Kim Sang Kyum SK Moon Dae Hyuk DH Lee Seung Jin SJ

Cell death & disease 20200529 5

System xc- contributes to glutathione (GSH) synthesis and protects cells against ferroptosis by importing cystine and exchanging it with glutamate. Transforming growth factor β1 (TGF-β1) induces redox imbalance; however, its role in system xc- regulation remains poorly understood. The present study was the first to show that TGF-β1 repressed the protein and mRNA levels of xCT, a catalytic subunit of system xc-, in PLC/PRF/5, Huh7, ...[more]

PMID: 32471991

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Project description:Rationale: Emerging evidence suggests that noncentrosomal microtubules play an essential role in intracellular transport, cell polarity and cell motility. Whether these noncentrosomal microtubules exist or function in cancer cells remains unclear. Methods: The expression and prognostic values of CAMSAP2 and its functional targets were analyzed by immunohistochemistry in two independent HCC cohorts. Immunofluorescence and co-immunoprecipitation were used for detection of CAMSAP2-decorated noncentrosomal microtubule. Chromatin immunoprecipitation and luciferase report assays were used to determine the c-Jun binding sites in HDAC6 promoter region. In vitro migration and invasion assays and in vivo orthotopic metastatic models were utilized to investigate invasion and metastasis. Results: We reported a microtubule minus‑end‑targeting protein, CAMSAP2, is significantly upregulated in hepatocellular carcinoma (HCC) and correlated with poor prognosis. CAMSAP2 was specifically deposited on microtubule minus ends to serve as a "seed" for noncentrosomal microtubule outgrowth in HCC cells. Upon depletion of CAMSAP2, the noncentrosomal microtubule array was transformed into a completely radial centrosomal pattern, thereby impairing HCC cell migration and invasion. We further demonstrated that CAMSAP2 cooperates with EB1 to regulate microtubule dynamics and invasive cell migration via Trio/Rac1 signaling. Strikingly, both immunofluorescence staining and western blotting showed that CAMSAP2 depletion strongly reduced the abundance of acetylated microtubules in HCC cells. Our results revealed that HDAC6, a promising target for cancer therapy, was inversely downregulated in HCC and uniquely endowed with tumor-suppressive activity by regulation CAMSAP2-mediated microtubule acetylation. Mechanistically, CAMSAP2 activates c-Jun to induce transrepression of HDAC6 through Trio-dependent Rac1/JNK pathway. Furthermore, NSC23766, a Rac1-specific inhibitor significantly inhibited CAMSAP2-mediated HCC invasion and metastasis. Conclusions: CAMSAP2 is functionally, mechanistically, and clinically oncogenic in HCC. Targeting CAMSAP2-mediated noncentrosomal microtubule acetylation may provide new therapeutic strategies for HCC metastasis.

Dataset Information

TGF-?1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells.

Publications

TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells.

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