A potential target for liver cancer management, lysophosphatidic acid receptor 6 (LPAR6), is transcriptionally up-regulated by the NCOA3 coactivator
| Autor: | Xinyi Zeng, Canhua Huang, Cong Liu, Liangyi Chen, Xuan Zheng, Lei Qiu, Mingtian Wei, Junhong Han, Yinghui Jia, Liangliang Xu |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cell signaling Mice Nude Mice SCID medicine.disease_cause Biochemistry Nuclear Receptor Coactivator 3 03 medical and health sciences Coactivator medicine Animals Humans Histone acetyltransferase activity Receptors Lysophosphatidic Acid Molecular Biology Cell Proliferation Mice Inbred BALB C 030102 biochemistry & molecular biology Hepatocyte Growth Factor Cell growth Chemistry LPAR6 Liver Neoplasms Hep G2 Cells Cell Biology Up-Regulation Gene Expression Regulation Neoplastic 030104 developmental biology Nuclear receptor coactivator 3 Cancer research Hepatocyte growth factor Carcinogenesis Signal Transduction medicine.drug |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra119.009899 |
| Popis: | Lysophosphatidic acid receptor 6 (LPAR6) is a G protein–coupled receptor that plays critical roles in cellular morphology and hair growth. Although LPAR6 overexpression is also critical for cancer cell proliferation, its role in liver cancer tumorigenesis and the underlying mechanism are poorly understood. Here, using liver cancer and matched paracancerous tissues, as well as functional assays including cell proliferation, quantitative real-time PCR, RNA-Seq, and ChIP assays, we report that LPAR6 expression is controlled by a mechanism whereby hepatocyte growth factor (HGF) suppresses liver cancer growth. We show that high LPAR6 expression promotes cell proliferation in liver cancer. More importantly, we find that LPAR6 is transcriptionally down-regulated by HGF treatment and that its transcriptional suppression depends on nuclear receptor coactivator 3 (NCOA3). We note that enrichment of NCOA3, which has histone acetyltransferase activity, is associated with histone 3 Lys-27 acetylation (H3K27ac) at the LPAR6 locus in response to HGF treatment, indicating that NCOA3 transcriptionally regulates LPAR6 through the HGF signaling cascade. Moreover, depletion of either LPAR6 or NCOA3 significantly inhibited tumor cell growth in vitro and in vivo (in mouse tumor xenograft assays), similar to the effect of the HGF treatment. Collectively, our findings indicate an epigenetic link between LPAR6 and HGF signaling in liver cancer cells, and suggest that LPAR6 can serve as a biomarker and new strategy for therapeutic interventions for managing liver cancer. |
| Databáze: | OpenAIRE |
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