PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control

Valcárcel-Jiménez, Lorea; Macchia, Alice; Crosas‐Molist, Eva; Schaub-Clerigué, Ariane; Camacho, Laura; Martín-Martín, Natalia; Cicogna, Paolo; Viera-Bardón, Cristina; Fernández-Ruiz, Sonia; Rodríguez-Hernández, Irene; Heřmanová, Ivana; Astobiza, Ianire; Cortazar, Ana R.; Corres-Mendizabal, Jon; Gómez-Muñoz, Antonio; Sanz-Moreno, Victoria; Torrano, Verónica; Carracedo, Arkaitz

doi:10.1158/0008-5472.can-19-1231

Cited by 49 publications

(45 citation statements)

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“…PGC1α was shown to induce transcription of several genes coding proteins involved in metabolic pathways, including those engaged in fatty acid catabolism [97]. Moreover, the activity of PGC1α-ERRα negatively correlated with levels of oncogenic transcription factor MYC [98]. However, it has to be added that the effect of PGC1α differs across various tumors (for review, see [99]).…”

Section: Slc22a5 and Fatty Acid Oxidation In Cancermentioning

confidence: 99%

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

Juraszek

Nałęcz

2019

Molecules

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Oxidation of fatty acids uses l-carnitine to transport acyl moieties to mitochondria in a so-called carnitine shuttle. The process of β-oxidation also takes place in cancer cells. The majority of carnitine comes from the diet and is transported to the cell by ubiquitously expressed organic cation transporter novel family member 2 (OCTN2)/solute carrier family 22 member 5 (SLC22A5). The expression of SLC22A5 is regulated by transcription factors peroxisome proliferator-activated receptors (PPARs) and estrogen receptor. Transporter delivery to the cell surface, as well as transport activity are controlled by OCTN2 interaction with other proteins, such as PDZ-domain containing proteins, protein phosphatase PP2A, caveolin-1, protein kinase C. SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for β-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation. On the other hand, SLC22A5 can also transport several chemotherapeutics used in clinics, leading to cancer cell death.

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Section: Slc22a5 and Fatty Acid Oxidation In Cancermentioning

confidence: 99%

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

Juraszek

Nałęcz

2019

Molecules

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“…Filtering those group/cohort relationships identified the most altered genes in the local tumor cohorts (MSKCC and TCGA). Overlapping identified commonly altered genes associated with PCa including ERG 35 (which was also altered at the protein level in the OICR cohort) and FGFR2 95 , but also identified others that were relatively under-investigated such as PPARGC1A 37 , 38 , 96 but associated with worse disease free survival, or uninvestigated in PCa, such as the metastasis suppressor PDLIM1 97 . Stable knockdown of PGC1α increased proliferation and invasion of LNCaP cells, and profoundly altered the transcriptome.…”

Section: Discussionmentioning

confidence: 99%

“…Earlier studies by Carracedo and colleagues identified reduced expression of PGC1α in PCa, and these workers pursued a strategy to over-express PGC1α in advanced PCa cell (PC-3) cells line and analyzed these effects in two impactful studies 37 , 38 . Their findings support a role for PGC1α to regulate a transcriptome that is regulated by PGC1α and ERRα cross-talk, which regulates MYC signaling to regulate invasiveness; indeed in the current study b-HLH motifs were identified in the PGC1α-binding sites identified in LNCaP cells.…”

Section: Discussionmentioning

confidence: 99%

“…These studies have revealed a number of high profile and common alterations in TFs and coregulators in PCa. For example, ERG 35 and NR3C1/GR 36 have been identified as commonly altered, whereas others such as the PPARγ coactivator PGC1α 37 , 38 are relatively under-investigated. However, given the multitude of TFs and coregulators, many have not been investigated at all in the context of PCa.…”

Section: Introductionmentioning

confidence: 99%

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Identification of transcription factor co-regulators that drive prostate cancer progression

Siddappa

Wani

Long

et al. 2020

Sci Rep

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In prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (r 0.4–0.55). In localized PCa, stringent expression filtering identified commonly altered TFs and coregulator genes, including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1α). Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~ 2300 genes; FDR < 0.05, logFC > 1.5), but only modestly impacted PPARγ responses. GSEA analyses of the PGC1α transcriptome revealed that it significantly altered the AR-dependent transcriptome, and was enriched for epigenetic modifiers. PGC1α-dependent genes were overlapped with PGC1α-ChIP-Seq genes and significantly associated in TCGA with higher grade tumors and worse disease-free survival. These methods and data demonstrate an approach to identify cancer-driver coregulators in cancer, and that PGC1α expression is clinically significant yet underexplored coregulator in aggressive early stage PCa.

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“…The development of tumor size leads to the many genomic alternations, including a mutation in function and structure of the genome, and these alternations depend on the tumor size and cancer-cell types [ 71 ]. Conventionally different strategies, including chemotherapies, have been used against these alternations, but they remain poorly characterized [ 72 ]. However, the CRISPR/Cas9 proves as a potential target against prostate cancer due to its limited off-target effects and high accuracy [ 10 ].…”

Section: The Potential Therapeutic Target Effects Of Crispr/cas9 In Smentioning

confidence: 99%

CRISPR/Cas9: A powerful genome editing technique for the treatment of cancer cells with present challenges and future directions

et al. 2020

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Cancer is one of the most leading causes of death and a major public health problem, universally. According to accumulated data, every year, approximately 8.5 million people died because of the lethality of cancer. Recently, a new RNA domain-containing endonuclease-based genome engineering technology, namely the clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein-9 (Cas9) have been proved as a powerful technique in the treatment of cancer due to its multifunctional properties including high specificity, accuracy, time reducing and cost-effective strategies with minimum off-target effects. The present review investigates the overview of recent studies on the newly developed genome-editing strategy, CRISPR/Cas9, as an excellent pre-clinical therapeutic option in the reduction and identification of new tumor target genes in the solid tumors. Based on accumulated data, we revealed that CRISPR/Cas9 significantly inhibited the robust tumor cell growth (breast, lung, liver, colorectal, and prostate) by targeting the oncogenes, tumor-suppressive genes, genes associated to therapies by inhibitors, and genes associated to chemotherapies drug resistance, and suggested that CRISPR/Cas9 could be a potential therapeutic target in inhibiting the tumor cell growth by suppressing the cell-proliferation, metastasis, invasion and inducing the apoptosis during the treatment of malignancies in the near future. The present review also discussed the current challenges, and barriers and proposed future recommendations for a better understanding.

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PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control

Cited by 49 publications

References 50 publications

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

Identification of transcription factor co-regulators that drive prostate cancer progression

CRISPR/Cas9: A powerful genome editing technique for the treatment of cancer cells with present challenges and future directions

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