ACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis.
Ziqing YangShaomin ZouYijing ZhangJieping ZhangPeng ZhangLishi XiaoYunling XieManqi MengJunyan FengLiang KangMong-Hong LeeLekun FangPublished in: Nature communications (2023)
Gastric cancer (GC), one of the most common malignant tumors in the world, exhibits a rapid metastasis rate and causes high mortality. Diagnostic markers and potential therapeutic targets for GCs are urgently needed. Here we show that Actin-like protein 6 A (ACTL6A), encoding an SWI/SNF subunit, is highly expressed in GCs. ACTL6A is found to be critical for regulating the glutathione (GSH) metabolism pathway because it upregulates γ-glutamyl-cysteine ligase catalytic subunit (GCLC) expression, thereby reducing reactive oxygen species (ROS) levels and inhibiting ferroptosis, a regulated form of cell death driven by the accumulation of lipid-based ROS. Mechanistic studies show that ACTL6A upregulates GCLC as a cotranscription factor with Nuclear factor (erythroid-derived 2)-like 2 (NRF2) and that the hydrophobic region of ACTL6A plays an important role. Our data highlight the oncogenic role of ACTL6A in GCs and indicate that inhibition of ACTL6A or GCLC could be a potential treatment strategy for GCs.
Keyphrases
- cell death
- reactive oxygen species
- nuclear factor
- toll like receptor
- cell cycle arrest
- transcription factor
- oxidative stress
- signaling pathway
- fluorescent probe
- type diabetes
- cardiovascular events
- coronary artery disease
- ionic liquid
- electronic health record
- immune response
- mass spectrometry
- deep learning
- combination therapy
- replacement therapy
- binding protein
- gas chromatography
- data analysis
- simultaneous determination