HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

Zhou, Xianfei; Guo, Xiaomao; Chen, Meiyuan; Xie, Chencheng; Jiang, Jianxin

doi:10.1158/1541-7786.mcr-17-0256

Cited by 54 publications

(44 citation statements)

References 39 publications

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“…24,55 Moreover, it is known that HIF3A overexpression in pancreatic cancer tissues is correlated with a shorter survival time and increased local invasion and distant metastasis. 56 Further studies of HIF3A in this context are warranted.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13 C 5 -glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals ($7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.

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Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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“…*p < 0.05, **p < 0.01, ***p < 0.001, two-tailed Student's t test ◂ HEK293 and U2OS cell lines [30]. Furthermore, HIF-3α has been implicated in the progression of pancreatic cancer by directly binding the promoters of RHOC and ROCK1 and transactivating the RhoC-ROCK1 pathway in cancer cells that overexpress HIF3A [41].…”

Section: Discussionmentioning

confidence: 99%

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

Tolonen

Heikkilä

Malinen

et al. 2019

Cell. Mol. Life Sci.

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Hypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis with hundreds of hypoxiainducible target genes. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered a negative regulator of the hypoxia response pathway. However, the human HIF3A mRNA is subject to complex alternative splicing. It was recently shown that the long HIF-3α variants can form αβ dimers that possess transactivation capacity. Here, we show that overexpression of the long HIF-3α2 variant induces the expression of a subset of genes, including the erythropoietin (EPO) gene, while simultaneous downregulation of all HIF-3α variants by siRNA targeting a shared HIF3A region leads to downregulation of EPO and additional genes. EPO mRNA and protein levels correlated with HIF3A silencing and HIF-3α2 overexpression. Chromatin immunoprecipitation analyses showed that HIF-3α2 binding associated with canonical hypoxia response elements in the promoter regions of EPO. Luciferase reporter assays showed that the identified HIF-3α2 chromatin-binding regions were sufficient to promote transcription by all three HIF-α isoforms. Based on these data, HIF-3α2 is a transcription activator that directly regulates EPO expression.

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“…RhoC has also been found to promote tumor progression in several cancer types. For example, in pancreatic cancer, HIF‐3α was shown to transcriptionally regulate RhoC‐Rho‐associated protein kinase 1 signaling to promote invasion and metastasis in a Balb/c mouse model . Further, induction of RhoC and TNF‐α expression by downregulation of miR‐509 significantly enhanced brain metastasis of breast cancer cells in mice .…”

Section: Discussionmentioning

confidence: 99%

“…For example, in pancreatic cancer, HIF-3α was shown to transcriptionally regulate RhoC-Rho-associated protein kinase 1 signaling to promote invasion and metastasis in a Balb/c mouse model. 33 Further, induction of RhoC and TNF-α expression by downregulation of miR-509 significantly enhanced brain metastasis of breast cancer cells in mice. 53 Rac1 was shown to be required for two different mTORC2 signaling pathways in HER2+ breast cancer to drive metastasis.…”

Section: Complex Role Of Gtpases In Metastasismentioning

confidence: 96%

“…30 Extensive studies have shown that small GTPases such as RhoA, RhoC, Ras-related C3 botulinum toxin substrate 1 (Rac1), and cell division control protein 42 homolog (Cdc42) are induced in vitro under hypoxia to promote a metastatic phenotype. [31][32][33] Hypoxic induction and activation of RhoA and Rho-associated protein kinase 1 (ROCK1) by HIFs in breast cancer cells were shown to stimulate cell contraction, cell-induced matrix contraction, formation of focal adhesions, FAK activation, and thus an increased cell motility. 31 Moreover, activation of this signaling pathway in breast cancer patients was associated with decreased survival.…”

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confidence: 99%

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RhoB is regulated by hypoxia and modulates metastasis in breast cancer

Godet

DiGiacomo

et al. 2019

Cancer Reports

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Background RhoB is a Rho family GTPase that is highly homologous to RhoA and RhoC. RhoA and RhoC have been shown to promote tumor progression in many cancer types; however, a distinct role for RhoB in cancer has not been delineated. Additionally, several well‐characterized studies have shown that small GTPases such as RhoA, Rac1, and Cdc42 are induced in vitro under hypoxia, but whether and how hypoxia regulates RhoB in breast cancer remains elusive. Aims To determine whether and how hypoxia regulates RhoB expression and to understand the role of RhoB in breast cancer metastasis. Methods We investigated the effects of hypoxia on the expression and activation of RhoB using real‐time quantitative polymerase chain reaction and western blotting. We also examined the significance of both decreased and increased RhoB expression in breast cancer using CRISPR depletion of RhoB or a vector overexpressing RhoB in 3D in vitro migration models and in an in vivo mouse model. Results We found that hypoxia significantly upregulated RhoB mRNA and protein expression resulting in increased levels of activated RhoB. Both loss of RhoB and gain of RhoB expression led to reduced migration in a 3D collagen matrix and invasion within a multicellular 3D spheroid. We showed that neither the reduction nor overexpression of RhoB affected tumor growth in vivo. While the loss of RhoB had no effect on metastasis, RhoB overexpression led to decreased metastasis to the lungs, liver, and lymph nodes of mice. Conclusion Our results suggest that RhoB may have an important role in suppressing breast cancer metastasis.

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HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

Cited by 54 publications

References 39 publications

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

RhoB is regulated by hypoxia and modulates metastasis in breast cancer

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