A potential target for liver cancer management, lysophosphatidic acid receptor 6 (LPAR6), is transcriptionally up-regulated by the NCOA3 coactivator

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.

Lysophosphatidic acid receptor 6 regulated by miR-27a-3p attenuates tumor proliferation in breast cancer

“…GPCRs account for 34% of small molecular drug targets in diseases [ 47 ]. As a sub-family of GPCRs, LPAR6 has the potential to be targeted for disease therapy; it exhibits different roles in different organs affected by cancer [ 12 , 13 , 17 – 19 , 21 , 22 ]. Our results also support its diverse, even opposite, functions in different cancers (Fig.…”

“…As an oncogene, LPAR6 expression is increased in tumors compared with that in para-tumors or normal tissues. It promotes cancer initiation and progression and enhances cancer cell motility, invasion, and colony formation in liver cancer, pancreatic cancer, ovarian cancer, and prostate cancer [ 12 , 19 , 22 ]. In contrast, LPAR6 may act as an antitumor factor and inhibit cancer cell motility in colon cancer [ 14 ], and this antitumor role may exist in breast cancer [ 13 ].…”

“…Previous studies have suggested that LPAR6 affects tumor biological functions through Gα12/13-Rho, adenylyl cyclase (AC)/cyclic adenosine monophosphate-dependent/protein kinase A (PKA), Ca 2+ -protein kinase C (PKC) pathways, and that it is regulated by nuclear receptor coactivator 3 (NCOA3) [ 10 , 22 ]. To realize other potential mechanisms underlying the effects of LPAR6 on breast cancer, we performed GSEA using TCGA and METABRIC datasets.…”

“…LPAR1-5 have been well documented; however, LPAR6 is relatively poorly studied [11,15]. LPAR6 was first reported in hypotrichosis simplex [16] and afterwards was implicated in the initiation and progression of cancer [13,14,[17][18][19][20][21][22]. LPAR6 functions to reduce intestinal cell adhesion through binding to specific GPCRs, Gαi, or Gα12/13 and regulates downstream extracellular signal-regulated kinase 1/2 (ERK1/2) and Rho/ Rho-associated kinase (ROCK) pathways [15].…”

Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

“…LPAR6 expression in hepatocellular carcinoma correlated with poorer survival [ 80 ] and increased microvascular invasion [ 81 ]. Moreover, LPAR6 promotes hepatocellular carcinoma proliferation via the NCOA3-LPAR6-HGF signaling cascade, and the tumor-suppressive effect by depletion of LPAR6 is similar to that of anti-HGF treatment [ 82 ]. In pancreatic cancer, LPAR6 knockdown also inhibited cancer invasion and colony formation [ 67 ].…”