GRK6 Depletion Induces HIF Activity in Lung Adenocarcinoma
Sumei Yao1, Ayse Ertay2, Yilu Zhou2,3
1Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, China.
Abstract:
G protein-coupled receptor kinase 6 (GRK6) is expressed in various tissues and is involved in the development of several diseases including lung cancer. We previously reported that GRK6 is down-regulated in lung adenocarcinoma patients, which induces cell invasion and metastasis. However, further understanding of the role of GRK6 in lung adenocarcinoma is required. Here we explored the functional consequence of GRK6 inhibition in lung epithelial cells. Analysis of TCGA data was coupled with RNA sequencing (RNA-seq) in alveolar epithelial type II (ATII) cells following depletion of GRK6 with RNA interference (RNAi). Findings were validated in ATII cells followed by tissue microarray analysis. Pathway analysis suggested that one of the Hallmark pathways enriched upon GRK6 inhibition is 'Hallmark_Hypoxia' (FDR = 0.014). We demonstrated that GRK6 depletion induces HIF1α (hypoxia-inducible factor 1 alpha) levels and activity in ATII cells. The findings were further confirmed in lung adenocarcinoma samples, in which GRK6 expression levels negatively and positively correlate with HIF1α expression (P = 0.015) and VHL expression (P < 0.0001), respectively. Mechanistically, we showed the impact of GRK6 on HIF activity could be achieved via regulation of VHL levels. Taken together, targeting the HIF pathway may provide new strategies for therapy in GRK6-depleted lung adenocarcinoma patients.
Insights
G protein-coupled receptor kinase 6 (GRK6) down-regulation in lung adenocarcinoma promotes cancer progression by activating the hypoxia pathway. Targeting this pathway may offer new therapeutic strategies for patients with low GRK6 expression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- G protein-coupled receptor kinase 6 (GRK6) plays a role in various diseases, including lung cancer.
- GRK6 is downregulated in lung adenocarcinoma, correlating with increased cell invasion and metastasis.
- Further investigation into GRK6's function in lung adenocarcinoma is necessary.
Purpose of the Study:
- To explore the functional consequences of GRK6 inhibition in lung epithelial cells.
- To elucidate the molecular mechanisms by which GRK6 affects lung adenocarcinoma progression.
- To identify potential therapeutic targets for GRK6-deficient lung adenocarcinoma.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) data.
- RNA sequencing (RNA-seq) in alveolar epithelial type II (ATII) cells after GRK6 depletion via RNA interference (RNAi).
- Validation in ATII cells and tissue microarray analysis; pathway and correlation analyses.
Main Results:
- GRK6 inhibition enriched the 'Hallmark_Hypoxia' pathway.
- GRK6 depletion increased hypoxia-inducible factor 1 alpha (HIF1α) levels and activity in ATII cells.
- GRK6 expression negatively correlates with HIF1α and positively with VHL (von Hippel-Lindau) expression in lung adenocarcinoma samples.
Conclusions:
- GRK6 regulates HIF1α activity, potentially via VHL levels.
- Targeting the hypoxia pathway presents a potential therapeutic strategy for GRK6-depleted lung adenocarcinoma.
- Understanding the GRK6-HIF1α axis offers insights into lung adenocarcinoma pathogenesis.
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