| First Author | Zhou Y | Year | 2023 |
| Journal | Hepatology | Volume | 77 |
| Issue | 4 | Pages | 1106-1121 |
| PubMed ID | 35344606 | Mgi Jnum | J:360573 |
| Mgi Id | MGI:7834573 | Doi | 10.1002/hep.32487 |
| Citation | Zhou Y, et al. (2023) Malignant progression of liver cancer progenitors requires lysine acetyltransferase 7-acetylated and cytoplasm-translocated G protein GalphaS. Hepatology 77(4):1106-1121 |
| abstractText | BACKGROUND AND AIMS: Hepatocarcinogenesis goes through HCC progenitor cells (HcPCs) to fully established HCC, and the mechanisms driving the development of HcPCs are still largely unknown. APPROACH AND RESULTS: Proteomic analysis in nonaggregated hepatocytes and aggregates containing HcPCs from a diethylnitrosamine-induced HCC mouse model was screened using a quantitative mass spectrometry-based approach to elucidate the dysregulated proteins in HcPCs. The heterotrimeric G stimulating protein alpha subunit (GalphaS) protein level was significantly increased in liver cancer progenitor HcPCs, which promotes their response to oncogenic and proinflammatory cytokine IL-6 and drives premalignant HcPCs to fully established HCC. Mechanistically, GalphaS was located at the membrane inside of hepatocytes and acetylated at K28 by acetyltransferase lysine acetyltransferase 7 (KAT7) under IL-6 in HcPCs, causing the acyl protein thioesterase 1-mediated depalmitoylation of GalphaS and its cytoplasmic translocation, which were determined by GalphaS K28A mimicking deacetylation or K28Q mimicking acetylation mutant mice and hepatic Kat7 knockout mouse. Then, cytoplasmic acetylated GalphaS associated with signal transducer and activator of transcription 3 (STAT3) to impede its interaction with suppressor of cytokine signaling 3, thus promoting in a feedforward manner STAT3 phosphorylation and the response to IL-6 in HcPCs. Clinically, GalphaS, especially K28-acetylated GalphaS, was determined to be increased in human hepatic premalignant dysplastic nodules and positively correlated with the enhanced STAT3 phosphorylation, which were in accordance with the data obtained in mouse models. CONCLUSIONS: Malignant progression of HcPCs requires increased K28-acetylated and cytoplasm-translocated GalphaS, causing enhanced response to IL-6 and driving premalignant HcPCs to fully established HCC, which provides mechanistic insight and a potential target for preventing hepatocarcinogenesis. |
