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High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma.

ABSTRACT:

Background

Long-chain acyl-CoA synthetase-4 (ACSL4) is involved in fatty acid metabolism, and aberrant ACSL4 expression could be either tumorigenic or tumor-suppressive in different tumor types. However, the function and clinical significance of ACSL4 in lung adenocarcinoma remain elusive.

Results

ACSL4 was frequently downregulated in lung adenocarcinoma when analyzing both the TCGA database and the validation samples, and the lower ACSL4 expression was correlated with a worse prognosis. Using gene set enrichment analysis, we found that high ACSL4 expression was frequently associated with the oxidative stress pathway, especially ferroptosis-related proteins. In vitro functional studies showed that knockdown of ACSL4 increased tumor survival/invasiveness and inhibited ferroptosis, while ACSL4 overexpression exhibited the opposite effects. Moreover, high-fat treatment could also inhibit erastin-induced ferroptosis by affecting ACSL4 expression. The anti-tumor effects of ferroptosis inducers and the anti-ferroptosis effects of the high-fat diet were further validated using the mouse xenograft model.

Conclusions

ACSL4 plays a tumor-suppressive role in lung adenocarcinoma by suppressing tumor survival/invasiveness and promoting ferroptosis. Our study provided a theoretical reference for the application of ferroptotic inducers and dietary guidance for lung adenocarcinoma patients.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8166005 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Head and neck squamous cell carcinoma (HNSCC) is currently one of the most common malignancies with a poor prognosis worldwide. Meanwhile, small ubiquitin‑like modifier (SUMO) specific peptidase 1 (SENP1) was associated with ferroptosis. However, the specific functions and underlying mechanisms of action of SENP1 in ferroptosis and tumor progression of HNSCC remain to be established. The findings of the present study implicated a novel ferroptosis pathway in the initiation and progression of HNSCC, providing new functional targets to guide future therapy. In the present study, The Cancer Genome Atlas database was employed to establish a gene model related to ferroptosis and verified SENP1 as a key gene via transcriptome sequencing. Expression of SENP1 in HNSCC tissue and CAL‑27 cells was detected based on reverse transcription‑quantitative PCR and western blot analysis. Proliferation and migration abilities of cells were determined using Cell Counting Kit‑8, wound healing and Transwell experiments. Expression levels of iron, glutathione (GSH) and lipid peroxidation end‑product malondialdehyde (MDA) under conditions of silencing of SENP1 with shRNA lentivirus were assayed. Additionally, the relationship between SENP1 and long‑chain acyl‑coenzyme A synthase 4 (ACSL4) was validated with the aid of immunoblotting and co‑immunoprecipitation (co‑IP). Finally, the influence of shSENP1 on the expression of key ferroptosis proteins, glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11, was evaluated via western blotting. It was revealed that SENP1 was significantly overexpressed in HNSCC and associated with low patient survival. Silencing of SENP1 led to significant suppression of cell proliferation, migration and invasion, increase in the contents of iron ions and MDA and decline in GSH levels in HNSCC cells, thereby enhancing ferroptosis and inhibiting disease progression. Conversely, overexpression of SENP1 suppressed ferroptosis and promoted progression of HNSCC. Co‑IP and western blot analyses revealed a SUMOylation link between SENP1 and ACSL4. SENP1 reduced the stability of ACSL4 protein through deSUMOylation, leading to inhibition of ferroptosis. SENP1 silencing further inhibited the expression of the key iron death protein, GPX4, to regulate ferroptosis. Taken together, SENP1 deficiency promoted ferroptosis and inhibited tumor progression through reduction of SUMOylation of ACSL4 in HNSCC. The collective results of the present study supported the utility of SENP1 as an effective predictive biomarker for targeted treatment of HNSCC.