Alpha-fetoprotein upregulates hepatocellular carcinoma cell-intrinsic PD-1 expression through the LATS2/YAP/TEAD1 pathway

• Published in: Biochimica et biophysica acta. General subjects Vol. 1868; no. 5; p. 130592
• Main Authors: Leng, Guangxian, Gong, Hongxia, Liu, Guiyuan, Kong, Yin, Guo, Liuqing, Zhang, Youcheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2024
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AFP; alpha-Fetoproteins - metabolism; Carcinoma, Hepatocellular - metabolism; chromatin immunoprecipitation; death; domain; fluorescence; genes; HCC; hepatoma; Humans; LATS2; Liver Neoplasms - metabolism; luciferase; neoplasm progression; phosphorylation; Programmed Cell Death 1 Receptor - metabolism; Protein Serine-Threonine Kinases - genetics; quantitative polymerase chain reaction; TEA Domain Transcription Factors; TEAD1; transcription (genetics); Transcription Factors - genetics; Transcription Factors - metabolism; Tumor cell-intrinsic PD-1; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; YAP; NK cells; Tumor cell-intrinsic PD-1; IP; HCC; YAP; AFP; WB; ChIP; CYR61; LATS2; OE; PD-L1; KD; CO-IP; TEAD1; FC; IF; PD-1; RT-qPCR
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130592

Hepatocellular carcinoma (HCC) cell-intrinsic programmed death 1 (PD-1) promotes tumor progression. However, the mechanisms that regulate its expression are unclear. This study investigated the impact of alpha-fetoprotein (AFP) on HCC cell-intrinsic PD-1 expression. The expression of PD-1 and AFP at the gene and protein levels was detected using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). Proteins interacting with AFP were examined by co-immunoprecipitation (CO-IP). Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were used to identify transcription-enhanced association domain 1 (TEAD1) binding to the promoter of PD-1. The expression of HCC cell-intrinsic PD-1 was positively correlated with AFP. Mechanistically, AFP inhibited the phosphorylation of large tumor suppressor 2 (LATS2) and yes-associated protein (YAP). As a result, YAP is transferred to the nucleus and forms a transcriptional complex with TEAD1, promoting PD-1 transcription by binding to its promoter. AFP is an upstream regulator of the HCC cell-intrinsic PD-1 and increases PD-1 expression via the LATS2/YAP/TEAD1 axis. Our findings provide insight into the mechanisms of HCC development and offer new ideas for further in-depth studies of HCC. •Hepatocellular carcinoma (HCC) cells express programmed death protein 1 (PD-1).•HCC cell-intrinsic PD-1 expression is associated with alpha-fetoprotein (AFP).•The YAP/TEAD1 complex promotes HCC cell-intrinsic PD-1 transcription.•AFP enhances the transcriptional function of the YAP/TEAD1 complex via LATS2/YAP.•AFP upregulates HCC cell-intrinsic PD-1 transcription via the LATS2/YAP/TEAD1 axis.