The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

GRK6 depletion induces HIF activity in lung adenocarcinoma

GRK6 depletion induces HIF activity in lung adenocarcinoma
GRK6 depletion induces HIF activity in lung adenocarcinoma
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.
2234-943X
Yao, Sumei
5f6e480b-ce90-4bae-978f-2fcd50e06972
Ertay, Ayse
fdd0c5cb-cfb2-4e25-9343-cdc462035531
Zhou, Yilu
1878565d-39e6-467d-a027-7320bf4cdaf2
Yao, Liudi
3c9ce766-5334-49f7-9517-c4dc2013f933
Hill, Charlotte
6d1cfed3-11b1-48af-b171-b8726ab673eb
Chen, Jinliang
478ca062-b74c-4126-b203-90d57c327ac4
Guan, Yangbo
f48d8a78-e2c1-453d-846b-bf2afcc8595c
Sun, Hui
d0d50a35-8087-4313-acfc-0fa959a12854
Ewing, Robert
022c5b04-da20-4e55-8088-44d0dc9935ae
Liu, Yifei
1e83939f-9375-4303-9546-f060a17f9d04
Lv, Xuedong
db90748f-8cb2-4e5d-891f-6d8f0b48d6ae
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Yao, Sumei
5f6e480b-ce90-4bae-978f-2fcd50e06972
Ertay, Ayse
fdd0c5cb-cfb2-4e25-9343-cdc462035531
Zhou, Yilu
1878565d-39e6-467d-a027-7320bf4cdaf2
Yao, Liudi
3c9ce766-5334-49f7-9517-c4dc2013f933
Hill, Charlotte
6d1cfed3-11b1-48af-b171-b8726ab673eb
Chen, Jinliang
478ca062-b74c-4126-b203-90d57c327ac4
Guan, Yangbo
f48d8a78-e2c1-453d-846b-bf2afcc8595c
Sun, Hui
d0d50a35-8087-4313-acfc-0fa959a12854
Ewing, Robert
022c5b04-da20-4e55-8088-44d0dc9935ae
Liu, Yifei
1e83939f-9375-4303-9546-f060a17f9d04
Lv, Xuedong
db90748f-8cb2-4e5d-891f-6d8f0b48d6ae
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e

Yao, Sumei, Ertay, Ayse, Zhou, Yilu, Yao, Liudi, Hill, Charlotte, Chen, Jinliang, Guan, Yangbo, Sun, Hui, Ewing, Robert, Liu, Yifei, Lv, Xuedong and Wang, Yihua (2021) GRK6 depletion induces HIF activity in lung adenocarcinoma. Frontiers in Oncology. (In Press)

Record type: Article

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.

Text
Merged_GRK6 IN LUNG CANCER - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (3MB)

More information

Accepted/In Press date: 26 April 2021

Identifiers

Local EPrints ID: 448872
URI: http://eprints.soton.ac.uk/id/eprint/448872
ISSN: 2234-943X
PURE UUID: e4eb1265-bb46-4e1b-8b35-55950fe6ffce
ORCID for Robert Ewing: ORCID iD orcid.org/0000-0001-6510-4001
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

Catalogue record

Date deposited: 07 May 2021 16:32
Last modified: 08 May 2021 01:48

Export record

Contributors

Author: Sumei Yao
Author: Ayse Ertay
Author: Yilu Zhou
Author: Liudi Yao
Author: Charlotte Hill
Author: Jinliang Chen
Author: Yangbo Guan
Author: Hui Sun
Author: Robert Ewing ORCID iD
Author: Yifei Liu
Author: Xuedong Lv
Author: Yihua Wang ORCID iD

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×