Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Maaty, Mohamed A. Abu el; Terzic, Julie; Keime, Céline; Rovito, Daniela; Lutzing, Régis; Yanushko, Darya; Parisotto, Maxime; Grelet, Élise; Namer, Izzie Jacques; Lindner, Véronique; Laverny, Gilles; Metzger, Daniel

doi:10.1126/sciadv.abo2295

Cited by 25 publications

(30 citation statements)

References 66 publications

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“…35 Under the effects of HIF-1α, prostate intraepithelial neoplasia (PIN) cells highly express transglutaminase 2 (TGM2) and exhibit impaired androgen signaling, enhancing malignant progression. 23 In addition, some factors, such as Orai1; 134 phospholipase D2 (PLD2); 135 annexin A3 (ANXA3); 136 CXCR4; 137 cysteine-rich protein 2 (CSRP2); 138 hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP); 139 twist family bHLH transcription factor 2 (TWIST2); 140 and noncoding RNAs, such as long-stranded non-coding RNA (lncRNA) PVT1, 141 lncRNA-GAPLINC, 142 and LncRNA-MTA2TR; 143 and micro-RNAs, such as miR-525-5p, 144 miR-301a-3p, 145,146 and miR-141-3p, 147 play important roles in regulating hypoxia-induced cancer cell proliferation, migration, invasion, and angiogenesis in the TME under hypoxic conditions (Table 1).…”

Section: Hypoxia Signaling Pathways and Cancer Cells Hifs And Cancer ...mentioning

confidence: 99%

“…[19][20][21][22] Intra-tumor hypoxia is linked to decreased disease-free survival outcomes in several cancers including prostate, cervical cancer, and head and neck squamous cell carcinoma (HNSCC). [23][24][25][26] The hypoxic environment alters the expression levels of genes that modulate metabolism and other processes. Moreover, hypoxic signaling interacts with other cellular pathways to alter cancer cell malignant behaviors and is closely associated with cancer cell proliferation, migration, invasion and angiogenesis, and affects cancer treatment outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Zhou

Han

et al. 2023

Sig Transduct Target Ther

236

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Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy.

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Section: Hypoxia Signaling Pathways and Cancer Cells Hifs And Cancer ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Zhou

Han

et al. 2023

Sig Transduct Target Ther

236

View full text Add to dashboard Cite

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“…Supporting these results, in Pten Knockout PCa mouse models, the expression level of the glycolytic enzymes has been recently reported to be associated with the expression of luminal hypoxia-inducible factor 1 alpha (HIF-1α), and the expression of EZH2 and SOX2 in advanced stages of tumoral development. Moreover, luminal HIF-1α promotes the elevation of MDSCs-recruiting factors [ 249 ]. In addition, the metabolic reprograming in tumoral cells also involves lipid and amino acid metabolism [ 250 , 251 ], and in PCa, it has been shown that EZH2 is involved in the alteration of multiple metabolic pathways (reviewed in [ 250 ]).…”

Section: Role Of Ezh2 In Tumoral Metabolismmentioning

confidence: 99%

Polycomb Directed Cell Fate Decisions in Development and Cancer

Germán

Ellis

2022

Epigenomes

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The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify chromatin landscapes and control the expression of master transcriptional programs to determine cellular identity. The two mayor PcG protein complexes that have been identified in mammals to date are Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). These protein complexes selectively repress gene expression via the induction of covalent post-translational histone modifications, promoting chromatin structure stabilization. PRC2 catalyzes the histone H3 methylation at lysine 27 (H3K27me1/2/3), inducing heterochromatin structures. This activity is controlled by the formation of a multi-subunit complex, which includes enhancer of zeste (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). This review will summarize the latest insights into how PRC2 in mammalian cells regulates transcription to orchestrate the temporal and tissue-specific expression of genes to determine cell identity and cell-fate decisions. We will specifically describe how PRC2 dysregulation in different cell types can promote phenotypic plasticity and/or non-mutational epigenetic reprogramming, inducing the development of highly aggressive epithelial neuroendocrine carcinomas, including prostate, small cell lung, and Merkel cell cancer. With this, EZH2 has emerged as an important actionable therapeutic target in such cancers.

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“…We have previously shown that prostatic intraepithelial neoplasia (PIN) of Pten (i)pe−/− mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is hypoxic and that enhanced hypoxia‐inducible factor 1 (HIF1) signaling in luminal cells drives the malignant evolution of such lesions (Abu El Maaty et al , 2022 ). In this study, we analyzed the molecular underpinnings enabling luminal cell survival in tumors of Pten (i)pe−/− mice under androgen deprivation conditions and found that castration resistance is associated with further activation of hypoxic signaling and a shift in luminal cell state.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors

et al. 2023

Self Cite

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Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone-independent state termed castrationresistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten (i)peÀ/À mice, generated by luminal epithelial cell-specific deletion of the tumor suppressor PTEN after puberty, is castrationresistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia-inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of Pten (i)peÀ/À mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten-deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management.

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Hypoxia-mediated stabilization of HIF1A in prostatic intraepithelial neoplasia promotes cell plasticity and malignant progression

Cited by 25 publications

References 66 publications

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Polycomb Directed Cell Fate Decisions in Development and Cancer

Hypoxia‐inducible factor 1A inhibition overcomes castration resistance of prostate tumors

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