Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy

Geng, Hao; Xue, Changhui; Mendonca, Janet; Sun, Xiao Xin; Liu, Qiong; Reardon, Patrick N.; Chen, Yingxiao; Qian, Kendrick; Hua, Vivian; Chen, Alice; Pan, Freddy; Yuan, Julia; Dang, Sang; Beer, Tomasz M.; Dai, Mu Shui; Kachhap, Sushant K.; Qian, David Z.

doi:10.1038/s41467-018-07411-7

Cited by 48 publications

(63 citation statements)

References 56 publications

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“…The finding suggests the signaling pathways act independently and regulate the expression of different subsets of genes. Other studies have reported both positive and negative crosstalk between androgen/AR and hypoxia/HIF1a [26, 28, 29]. Globally there were substantially more AR binding sites than HIF binding sites, demonstrating androgen signaling dominance over HIF signaling in the prostate cancer cells studied.…”

Section: Discussionmentioning

confidence: 70%

“…Hypoxia and HIF have already been implicated in the development and progression of CRPC [24, 25]. Hypoxia was shown to induce AR independence and confer resistance to ADT through a metabolic switch favoring glycolysis [26]. Pseudohypoxia has also been linked to the metabolic switch from oxidative phosphorylation to glycolysis [27].…”

Section: Discussionmentioning

confidence: 99%

“…Crosstalk between the AR and hypoxia/HIF has been reported. ADT in hypoxia promotes adaptive androgen/AR-independence, and confers resistance to androgen/AR-targeted therapy (Geng et al 2018). Co-immunoprecipitation assays have confirmed a direct interaction between AR and HIF1a, and ChIP analysis showed HIF1a interacts with the AR on the PSA gene promoter [9].…”

Section: Introductionmentioning

confidence: 99%

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Independence of HIF1a and androgen signaling pathways in prostate cancer

Tran

Bibby

Yang

et al. 2019

Preprint

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Androgen signaling drives prostate cancer progression and is a therapeutic target.Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Independence of HIF1a and androgen signaling pathways in prostate cancer

Tran

Bibby

Yang

et al. 2019

Preprint

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“…Hypoxia is a typical characteristic of prostate cancer and is a major pathological factor attributing to castration resistance and the metastasis of prostate cancer [1]. When suffering the hypoxic environments, prostate cancer cells regulate a series of gene expression and the corresponding pathways that were essential for cell survival and stress adaptation [2]. Previous researches reported that hypoxia strongly attributed to the poor prognosis and malignancy of prostate cancer [3,4].…”

Section: Introductionmentioning

confidence: 99%

Suppression of TRPM7 Inhibited Hypoxia-Induced Migration and Invasion of Androgen-Independent Prostate Cancer Cells by Enhancing RACK1-Mediated Degradation of HIF-1α

Yang

Cai

Zhan

et al. 2020

Oxidative Medicine and Cellular Longevity

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Transient receptor potential melastatin subfamily member 7 (TRPM7) was essential in the growth and metastatic ability of prostate cancer cells. However, the effects and the relevant molecular mechanisms of TRPM7 on metastasis of prostate cancer under hypoxic atmosphere remain unclear. This study investigated the role of TRPM7 in the metastatic ability of androgen-independent prostate cancer cells under hypoxia. First, data mining was carried out to disclose the relationship between the TRPM7 gene level and the survival of prostate cancer patients. Specific siRNAs were used to knockdown target genes. Western blotting and qPCR were employed to determine protein and gene expression, respectively. The gene transcription activity was evaluated by luciferase activity assay of promoter gene. The protein interaction was determined by coimmunoprecipitation. Wound healing and transwell assays were employed to evaluated cell migration and invasion, respectively. Open access database results showed that high expression of TRPM7 was closely related to the poor survival of prostate cancer patients. Hypoxia simultaneously increased TRPM7 expression and induced HIF-1α accumulation in androgen-independent prostate cancer cells. Knockdown of TRPM7 significantly promoted HIF-1α degradation through the proteasome and inhibited EMT changes in androgen-independent prostate cancer cells under hypoxic condition. Moreover, TRPM7 knockdown increased the phosphorylation of RACK1 and strengthened the interaction between RACK1 and HIF-1α but attenuated the binding of HSP90 to HIF-1α. Whereas knockdown of RACK1 increased the binding of HSP90 to HIF-1α. Furthermore, both TRPM7 and HIF-1α knockdown significantly suppressed hypoxia-induced Annexin A1 protein expression, and suppression of HIF-1α/Annexin A1 signaling significantly inhibited hypoxia-induced cell migration and invasion of androgen-independent prostate cancer cells. Our findings demonstrate that TRPM7 knockdown promotes HIF-1α degradation via an oxygen-independent mechanism involving increased binding of RAKC1 to HIF-1α, and TRPM7-HIF-1α-Annexin A1 signaling axis plays a crucial role in the EMT, cell migration, and invasion of androgen-independent prostate cancer cells under hypoxic conditions.

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“…Crosstalk between the AR and hypoxia/HIF has been reported. ADT in hypoxia promotes adaptive androgen/ AR-independence, and confers resistance to androgen/ AR-targeted therapy [18] . Co-immunoprecipitation assays have confirmed a direct interaction between AR and HIF1a, and ChIP analysis showed HIF1a interacts with the AR on the PSA gene promoter [19].…”

Section: Introductionmentioning

confidence: 99%

Independence of HIF1a and androgen signaling pathways in prostate cancer

et al. 2020

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Background: 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 noncastrated 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 ChIPseq. 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.

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Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy

Cited by 48 publications

References 56 publications

Independence of HIF1a and androgen signaling pathways in prostate cancer

Independence of HIF1a and androgen signaling pathways in prostate cancer

Suppression of TRPM7 Inhibited Hypoxia-Induced Migration and Invasion of Androgen-Independent Prostate Cancer Cells by Enhancing RACK1-Mediated Degradation of HIF-1α

Independence of HIF1a and androgen signaling pathways in prostate cancer

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