Abstract
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.
Highlights
Lysophosphatidic acid receptor 6 (LPAR6) is a G protein– coupled receptor that plays critical roles in cellular morphology and hair growth
We find that LPAR6 is transcriptionally down-regulated by hepatocyte growth factor (HGF) treatment and that its transcriptional suppression depends on nuclear receptor coactivator 3 (NCOA3)
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
Summary
Lysophosphatidic acid receptor 6 (LPAR6) is a G protein– coupled receptor that plays critical roles in cellular morphology and hair growth. Hepatocyte growth factor (HGF) is a multipotent cytokine secreted by mesenchymal cells, acting mainly on epithelial-derived cells [6] It binds to the c-Met receptor, activating tyrosine kinase cascade to regulate cellular physiological properties that endow an important role in angiogenesis, tissue regeneration, and tumorigenesis [7,8,9,10]. Lysophosphatidic acid receptor 6 (LPAR6), a G protein– coupled receptor that is highly expressed in epithelial cells and hair follicles, mediates cAMP accumulation and Rho-dependent cellular morphological changes [25, 26] Some mutations in this gene have been found to cause hypotrichosis [27, 28]. No correlation between NCOA3 and LPAR6 has been found so far
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