Lipid degradation promotes prostate cancer cell survival

Itkonen, Harri M.; Brown, Michael D.; Urbanucci, Alfonso; Tredwell, Gregory D.; Lau, Chung-Ho E; Barfeld, Stefan J; Hart, Claire A.; Guldvik, Ingrid Jenny; Takhar, Mandeep; Heemers, Hannelore V.; Erho, Nicholas; Bloch, Katarzyna; Davicioni, Elai; Derua, Rita; Waelkens, Etienne; Mohler, James L.; Clarke, Noel W.; Swinnen, Johan; Keun, Hector C.; Rekvig, Ole Petter; Mills, Ian G.

doi:10.18632/oncotarget.16123

Cited by 68 publications

(64 citation statements)

References 47 publications

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“…RARg loss profoundly altered AR regulated events including DHT-mediated antiproliferative effects 16 and reduced the sensitivity of the DHT-dependent transcriptome, notably by restricting the capacity of AR to repress MYC signaling. Recently MYC has been shown to antagonize AR function in prostate cells 32 , and the current study suggest that RARg regulates these events, in part through direct binding at the MYC locus.…”

Section: Discussionsupporting

confidence: 56%

The miR-96 and RARγ signaling axis governs androgen signaling and prostate cancer progression

Long

Singh

Russell

et al. 2017

Preprint

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RARg (RARG) expression is commonly reduced in prostate cancer (PCa). Modulating RARg levels, not retinoid ligand, had the biggest impact on prostate cell proliferation and gene expression. Genomic binding of the non-liganded, apo, RARg was significantly enriched at active enhancers, associated with AR, and RARg knockdown governed the AR capacity to regulate cell differentiation and gene-regulation. Altered RARg target genes expression in TCGA significantly associated with more aggressive PCa. RARg downregulation was explained by a stark and common increase in miR-96 in PCa cell and animal models, and human PCa.Biochemical approaches confirmed that miR-96 directly regulates RARG expression and function. Capture of the miR-96 targetome by biotin-miRNA pulldown identified a RARg-centric network significantly associated with more aggressive PCa and worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets an RARg network to govern AR signaling and its disruption is a cancer-driver. STATEMENT OF SIGNIFICANCE.We identified that miR-96 targets a RARg-network, which in turn regulates AR, PCa progression and disease outcome. These findings occur independently of retinoid ligand and reveal how miRNA govern nuclear receptor functions, and can be exploited to identify aggressive prostate cancer at an early stage.

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Section: Discussionsupporting

confidence: 56%

The miR-96 and RARγ signaling axis governs androgen signaling and prostate cancer progression

Long

Singh

Russell

et al. 2017

Preprint

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“…We further defined the biological roles of CENPF in PC3 cells. Fatty acid and lipid metabolism play critical roles in energy maintenance and cellular nutrition in cancer, particularly in PC [33,34]. Biosynthesis of fatty acids utilizes glucose and exploits a pathway that is mainly controlled by an enzyme, fatty acid synthase (FASN).…”

Section: Silencing Of Cenpf Impeded Epigenetic Modulation Of Histone mentioning

confidence: 99%

Centromere protein F (CENPF), a microtubule binding protein, modulates cancer metabolism by regulating pyruvate kinase M2 phosphorylation signaling

et al. 2018

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Prostate cancer (PC) is the most commonly diagnosed cancer in men and is the second leading cause of male cancer-related death in North America. Metabolic adaptations in malignant PC cells play a key role in fueling the growth and progression of the disease. Unfortunately, little is known regarding these changes in cellular metabolism. Here, we demonstrate that centromere protein F (CENPF), a protein associated with the centromere-kinetochore complex and chromosomal segregation during mitosis, is mechanically linked to altered metabolism and progression in PC. Using the CRISPR-Cas9 system, we silenced the gene for CENPF in human PC3 cells. These cells were found to have reduced levels of epithelial-mesenchymal transition markers and inhibited cell proliferation, migration, and invasion. Silencing of CENPF also simultaneously improved sensitivity to anoikis-induced apoptosis. Mass spectrometry analysis of tyrosine phosphorylated proteins from CENPF knockout (CENPF KO) and control cells revealed that CENPF silencing increased inactive forms of pyruvate kinase M2, a rate limiting enzyme needed for an irreversible reaction in glycolysis. Furthermore, CENPF KO cells had reduced global bio-energetic capacity, acetyl-CoA production, histone acetylation, and lipid metabolism, suggesting that CENPF is a critical regulator of cancer metabolism, potentially through its effects on mitochondrial functioning. Additional quantitative immunohistochemistry and imaging analyzes on a series of PC tumor microarrays demonstrated that CENPF expression is significantly increased in higher-risk PC patients. Based on these findings, we suggest the CENPF may be an important regulator of PC metabolism through its role in the mitochondria.

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“…Consequently, genetic changes in AR form one of the core contributors to altered cellular metabolism in PCa. C-MYC is another TF overexpressed in PCa, which partially overlaps with AR-binding sites and antagonises AR-mediated transcriptional output (Barfeld et al 2017). However, in molecular apocrine BCa, MYC cooperates with AR in androgen-responsive gene transcription contrary to the antagonistic relationship seen in PCa (Ni et al 2013).…”

Section: Metabolic Reprogramming In Prostate and Breast Cancermentioning

confidence: 99%

“…Consequently, PCa cells are vulnerable to inhibitors of lipid degradation like perhexiline or by ECI2 knockdown and respond by activating incomplete autophagy followed by cell death response. Moreover, the clinically approved drug perhexiline exhibited potent anti-tumour activity in combination with antiandrogen, enzalutamide and abiraterone acetate (Itkonen et al 2017). Fatty acid oxidation is also an important bioenergetic pathway in MYC-overexpressing triple-negative BCa (Camarda et al 2016).…”

Section: Androgens By Coordinating the Expression Of Enzymes Involvedmentioning

confidence: 99%

The impact of transcription on metabolism in prostate and breast cancers

Poulose¹,

Mills²,

Steele³

2018

Endocrine-Related Cancer

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Metabolic dysregulation is regarded as an important driver in cancer development and progression. The impact of transcriptional changes on metabolism has been intensively studied in hormone-dependent cancers, and in particular, in prostate and breast cancer. These cancers have strong similarities in the function of important transcriptional drivers, such as the oestrogen and androgen receptors, at the level of dietary risk and epidemiology, genetics and therapeutically. In this review, we will focus on the function of these nuclear hormone receptors and their downstream impact on metabolism, with a particular focus on lipid metabolism. We go on to discuss how lipid metabolism remains dysregulated as the cancers progress. We conclude by discussing the opportunities that this presents for drug repurposing, imaging and the development and testing of new therapeutics and treatment combinations.

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Lipid degradation promotes prostate cancer cell survival

Cited by 68 publications

References 47 publications

The miR-96 and RARγ signaling axis governs androgen signaling and prostate cancer progression

The miR-96 and RARγ signaling axis governs androgen signaling and prostate cancer progression

Centromere protein F (CENPF), a microtubule binding protein, modulates cancer metabolism by regulating pyruvate kinase M2 phosphorylation signaling

The impact of transcription on metabolism in prostate and breast cancers

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