Independence of HIF1a and androgen signaling pathways in prostate cancer

Maxine G B Tran,Thomas Carroll,Antonio Ramos-Montoya,Anne Y Warren,Ian G Mills,James Hadfield,Becky A S Bibby,Catharine M L West,Charlie Massie,Franklin Lo,David E Neal,Helen Scott,Deepa Shukla,Michelle Osborne,Lingjian Yang,Patrick Maxwell,Rory Stark

doi:10.1186/s12885-020-06890-6

Abstract

BackgroundTherapeutic 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.MethodsIn 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.ResultsAndrogen 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.ConclusionsThe 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.

Highlights

Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer
Androgen deprivation therapy (ADT) inhibits androgen receptor (AR) signaling by blocking the production of androgens or by inhibiting androgen binding to the AR
We show that the AR and hypoxia inducible factor (HIF)/hypoxia signaling pathways function independently regulating the transcription of different subsets of genes with few shared targets

Summary

Introduction

Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. 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. Androgen signaling drives prostate cancer development and progression. ADT is initially effective, resistance subsequently develops and the AR signaling pathway remains active even in the absence of endogenous androgens. The development of androgen independent or castrateresistant prostate cancer (CRPC) is associated with the presence of metastases and a rapid clinical demise [3]. Identifying which patients will progress to CRPC is a major challenge in the treatment of prostate cancer. Understanding the biology that underpins progression to CRPC will support the development of novel strategies to identify, prevent and treat CRPC

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Results