Independence of HIF1a and androgen signaling pathways in prostate cancer
Bibby, Becky A
West, Catharine ML
AffiliationUro-oncology Research Group, Cancer Research UK Cambridge Institute, Cambridge
MetadataShow full item record
AbstractBackground: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated. Methods: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq. Results: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic. Conclusions: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted. Keywords: Androgen signaling; HIF1a signaling; Hypoxia; Prostate cancer.
CitationTran MGB, Bibby BAS, Yang L, Lo F, Warren AY, Shukla D, et al. Independence of HIF1a and androgen signaling pathways in prostate cancer. BMC Cancer. 2020;20(1):469.
- Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells.
- Authors: Fernandez EV, Reece KM, Ley AM, Troutman SM, Sissung TM, Price DK, Chau CH, Figg WD
- Issue date: 2015 Jun
- Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.
- Authors: Jia L, Wu D, Wang Y, You W, Wang Z, Xiao L, Cai G, Xu Z, Zou C, Wang F, Teoh JY, Ng CF, Yu S, Chan FL
- Issue date: 2018 Jun
- Hypoxia enhances transcriptional activity of androgen receptor through hypoxia-inducible factor-1α in a low androgen environment.
- Authors: Mitani T, Yamaji R, Higashimura Y, Harada N, Nakano Y, Inui H
- Issue date: 2011 Jan
- Expression of the forkhead transcription factor FOXP1 is associated both with hypoxia inducible factors (HIFs) and the androgen receptor in prostate cancer but is not directly regulated by androgens or hypoxia.
- Authors: Banham AH, Boddy J, Launchbury R, Han C, Turley H, Malone PR, Harris AL, Fox SB
- Issue date: 2007 Jul 1
- Coordinated action of hypoxia-inducible factor-1α and β-catenin in androgen receptor signaling.
- Authors: Mitani T, Harada N, Nakano Y, Inui H, Yamaji R
- Issue date: 2012 Sep 28