HIF1A signaling selectively supports proliferation of breast cancer in the brain

Ebright, Richard Y.; Zachariah, Marcus; Micalizzi, Douglas S.; Wittner, Ben S.; Niederhoffer, Kira; Nieman, Linda T.; Chirn, Brian; Wiley, Devon F.; Wesley, Benjamin; Shaw, Brian; Nieblas-Bedolla, Edwin; Atlas, Lian; Szabolcs, Annamária; Iafrate, A. John; Toner, Mehmet; Ting, David T.; Brastianos, Priscilla K.; Haber, Daniel A.; Maheswaran, Shyamala

doi:10.1038/s41467-020-20144-w

Cited by 69 publications

(37 citation statements)

References 52 publications

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“…In addition to the increased PSPC1 expression in the monocytes of patients with OSA regulated by HIF1α transcriptional pathways, the high circulating PSPC1 levels found in these patients could contribute to a paracrine effect. Furthermore, it has been reported that hypoxia, by HIF1α, induces MMP2 expression in endothelial cells, cardiac fibroblasts, macrophages, and breast cancer cells [37][38][39][40]. Hypoxia also promoted TGFβ1/Smad signaling via HIF1α [41].…”

Section: Discussionmentioning

confidence: 98%

Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Díaz‐García

García-Tovar

Casitas

et al. 2021

Cancers

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As some evidence suggests that hypoxia might be an inducer of nuclear paraspeckle formation, we explore whether intermittent hypoxia (IH)-mediated paraspeckle protein-1 (PSPC1) overexpression might contribute to the activation of tumor growth factor (TGF)β-SMAD pathway in patients with obstructive sleep apnea (OSA). This activation would promote changes in intracellular signaling that would explain the increased cancer aggressiveness reported in these patients. Here, we show that patients with OSA exhibit elevated PSPC1 levels both in plasma and in monocytes. Our data suggest that PSPC1 is ultimately delivered to the plasma through its cleavage from OSA monocytes by matrix metalloproteinase-2 (MMP2). In addition, IH promotes PSPC1, TGFβ, and MMP2 expression in monocytes through the hypoxia-inducible factor. Lastly, both PSPC1 and TGFβ induce increased expression of genes that drive the epithelial-to-mesenchymal transition. Our study details the mechanism by which hypoxemia upmodulates the extracellular release of PSPC1 by means of MMP2, such that plasma PSPC1 together with TGFβ activation signaling further promotes tumor metastasis and supports cancer aggressiveness in patients with OSA.

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Section: Discussionmentioning

confidence: 98%

Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Díaz‐García

García-Tovar

Casitas

et al. 2021

Cancers

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“…These differences in hypoxia signaling may be maintained in CTCs after dissemination and intravasation via epigenetic mechanisms (38). This may explain why differences in hypoxia signaling have been shown to contribute to metastatic ability of clustered CTCs (39) and microenvironment-dependent organ-specific metastasis (40). Intriguingly, the majority of clustered CTCs from breast tumors show up-regulated hypoxia signaling (39).…”

Section: Discussionmentioning

confidence: 99%

Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer

Chang

Chen²,

Tsai³

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial−mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis.

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“…HIF1a up-regulates a number of genes that support tumor cells to adopt to the hypoxic microenvironment (5). HIF1a overexpression has been detected in solid tumors and is associated with the progression of a variety of cancers, including ovarian cancer (6), breast cancer (7), non-small cell lung cancer (8) and pancreatic cancer (9). Studies have shown that HIF1a affects the regulation of tumor cell proliferation, angiogenesis, apoptosis and chemotherapy resistance during tumor development (10).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1

Cao

Zeng

Pan³

et al. 2021

Front. Oncol.

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BackgroundHypoxia is associated with the development of pancreatic cancer (PC). However, genes associated with hypoxia response and their regulatory mechanism in PC cells were unclear. The current study aims to investigate the role of the hypoxia associated gene fucosyltransferase 11 (FUT11) in the progression of PC.MethodsIn the preliminary study, bioinformatics analysis predicted FUT11 as a key hypoxia associated gene in PC. The expression of FUT11 in PC was evaluated using quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. The effects of FUT11 on PC cells proliferation and migration under normoxia and hypoxia were evaluated using Cell Counting Kit 8, 5-ethynyl-2’-deoxyuridine (EDU) assay, colony formation assay and transwell assay. The effects of FUT11 in vivo was examined in mouse tumor models of liver metastasis and subcutaneous xenograft. Furthermore, Western blot, luciferase assay and immunoprecipitation were performed to explore the regulatory relationship among FUT11, hypoxia-inducible factor 1α (HIF1α) and pyruvate dehydrogenase kinase 1 (PDK1) in PC.ResultsFUT11 was markedly increased of PC cells with hypoxia, upregulated in the PC clinical tissues, and predicted a poor outcome of PC patients. Inhibition of FUT11 reduced PC cell growth and migratory ability of PC cells under normoxia and hypoxia conditions in vitro, and growth and tumor cell metastasis in vivo. FUT11 bound to PDK1 and regulated the expression PDK1 under normoxia and hypoxia. FUT11 interacted with PDK1 and decreased the ubiquitination of PDK1, lead to the activation of AKT/mTOR signaling pathway. FUT11 knockdown significantly increased the degradation of PDK1 under hypoxia, while treatment with MG132 can relieve the degradation of PDK1 induced by FUT11 knockdown. Overexpression of PDK1 in PC cells under hypoxia conditions reversed the suppressive impacts of FUT11 knockdown on PC cell growth and migration. In addition, HIF1α bound to the promoter of FUT11 and increased its expression, as well as co-expressed with FUT11 in PC tissues. Furthermore, overexpression of FUT11 partially rescued the suppressive effects of HIF1α knockdown on PC cell growth and migration in hypoxia condition.ConclusionOur data implicate that hypoxia-induced FUT11 contributes to proliferation and metastasis of PC by maintaining the stability of PDK1, thus mediating activation of AKT/mTOR signaling pathway, and suggest that FUT11 could be a novel and effective target for the treatment of pancreatic cancer.

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HIF1A signaling selectively supports proliferation of breast cancer in the brain

Cited by 69 publications

References 52 publications

Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer

Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1

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