Regulation of Mitochondrial Oxidative Metabolism by Tumor Suppressor FLCN

Hasumi, Hisashi; M, Baba; Hasumi, Yukiko; Huang, Ying; Oh, HyoungBin; Hughes, Robert M.; Klein, Mara E.; Takikita, Shoichi; Nagashima, Kunio; Schmidt, Laura S.; Linehan, W. Marston

doi:10.1093/jnci/djs418

Cited by 86 publications

(106 citation statements)

References 58 publications

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“…However, we could not detect PGC-1β protein using commercially available antibodies. In line with this work, it was previously reported that tumors from patients with BHD harbor an induced PGC-1α transcription profile associated with a high expression of mitochondria and OXPHOS-associated genes (17,27). Furthermore, PGC-1α and its target genes are consistently upregulated in 30 thyroid oncocytomas when compared with normal tissue (28).…”

Section: Increased Pgc-1α Expression In Flcn-null Cells Enhances Ros supporting

confidence: 82%

“…However, recent reports have shown that most cancer cells have normal mitochondrial function and that OXPHOS is not dispensable and actively contributes to energy and biosynthetic precursor production, which constitute a tumorigenic advantage (14)(15)(16). It has been reported recently that conditional loss of FLCN in mouse kidney and muscle resulted in increased mitochondrial function (17). To confirm this finding in our cellular model, we acutely measured the rate of mitochondrial respiration in Flcn KO MEFs compared with that in WT and Resc cells and show that loss of FLCN significantly increased total mitochondrial respiration (Figure 2A).…”

Section: Loss Of Flcn Increases Atp Levels Through Enhanced Hif-depenmentioning

confidence: 99%

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The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

et al. 2014

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The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPKdependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.

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Section: Increased Pgc-1α Expression In Flcn-null Cells Enhances Ros supporting

confidence: 82%

Section: Loss Of Flcn Increases Atp Levels Through Enhanced Hif-depenmentioning

confidence: 99%

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

et al. 2014

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“…21 Interestingly, FLCN has been recently demonstrated to act as a negative regulator of PGC1a expression levels both in conditional FLCN knockout mice and in cell models, 13 reinforcing the hypothesis of an involvement in oncocytic transformation also in a context different from BHD, such as CS. Alterations in gene expression levels due to genetic changes of the two non-canonical TSGs FLCN and PTEN, which act on converging pathways, may thus either cause oncocytic transformation after the occurrence of an oncogenic triggering event, or account for a primary transformation along with the appearance of an oncocytic phenotype.…”

Section: Discussionmentioning

confidence: 80%

“…4 Moreover, FLCN has been shown to negatively correlate with PGC1a activation, indicating that a decrease of the functional protein may induce mitochondrial biogenesis. 12,13 We performed a comprehensive genetic analysis of two oncocytic tumours, developed by a BHD and a CS patient, and observed a mirrored genetic background that may account for the development of oncocytic features of syndrome-associated tumours.…”

Section: Introductionmentioning

confidence: 99%

Where Birt–Hogg–Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours

et al. 2013

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Birt-Hogg-Dubè (BHD) is an autosomal dominant syndrome characterised by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cancer. The association of benign cutaneous lesions and increased cancer risk is also a feature of Cowden Syndrome (CS), an autosomal dominant disease caused by PTEN mutations. BHD and CS patients may develop oncocytomas, rare neoplasias that are phenotypically characterised by a prominent mitochondrial hyperplasia. We here describe the genetic analysis of a parotid and a thyroid oncocytoma, developed by a BHD and a CS patient, respectively. The BHD lesion was shown to maintain the wild-type allele of FLCN, while losing one PTEN allele. On the other hand, a double heterozygosity for the same two genes was found to be the only detectable tumorigenic hit in the CS oncocytoma. Both conditions occurred in a context of high chromosomal stability, as highlighted by comparative genomic hybridisation analysis. We conclude that, similarly to PTEN, FLCN may not always follow the classical Two Hits model of tumorigenesis and may hence belong to a class of non-canonical tumour suppressor genes. We hence introduce a role of PTEN/FLCN double heterozygosity in syndromic oncocytic tumorigenesis, suggesting this to be an alternative determinant to pathogenic mitochondrial DNA mutations, which are instead the genetic hallmark of sporadic oncocytic tumours.

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“…In accordance, heightened glycogen levels were also reported in the muscle tissues of muscle-specific Flcn KO mice as compared to the controls. 21,22 A dual role for glycogen…”

Section: The Glycogen Accumulation Conferred By Loss Of Flcn-1 Is Evomentioning

confidence: 99%

Glycogen: A must have storage to survive stressful emergencies

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2016

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Mechanisms of adaptation to acute changes in osmolarity are fundamental for life. When exposed to hyperosmotic stress, cells and organisms utilize conserved strategies to prevent water loss and maintain cellular integrity and viability. The production of glycerol is a common strategy utilized by the nematode Caenorhabditis elegans (C. elegans) and many other organisms to survive hyperosmotic stress. Specifically, the transcriptional upregulation of glycerol-3-phosphate dehydrogenase, a rate-limiting enzyme in the production of glycerol, has been previously implicated in many model organisms. However, what fuels this massive and rapid production of glycerol upon hyperosmotic stress has not been clearly elucidated. We have recently discovered an AMPK-dependent pathway that mediates hyperosmotic stress resistance in C. elegans. Specifically, we demonstrated that the chronic activation of AMPK leads to glycogen accumulation, which under hyperosmotic stress exposure, is rapidly degraded to mediate glycerol production. Importantly, we demonstrate that this strategy is utilized by flcn-1 mutant C. elegans nematodes in an AMPKdependent manner. FLCN-1 is the worm homolog of the human renal tumor suppressor Folliculin (FLCN) responsible for the Birt-Hogg-Dub e neoplastic syndrome. Here, we comment on the dual role for glycogen in stress resistance: it serves as an energy store and a fuel for osmolyte production. We further discuss the potential utilization of this mechanism by organisms in general and by human cancer cells in order to survive harsh environmental conditions and notably hyperosmotic stress.

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Regulation of Mitochondrial Oxidative Metabolism by Tumor Suppressor FLCN

Cited by 86 publications

References 58 publications

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

Where Birt–Hogg–Dubé meets Cowden Syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours

Glycogen: A must have storage to survive stressful emergencies

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