Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression

Klomp, Jeff; Petillo, David; Niemi, Natalie M.; Dykema, Karl; Chen, Jindong; Yang, Ximing J.; Sääf, Annika; Zickert, Peter; Aly, Markus; Bergerheim, Ulf S.R.; Nordenskjöld, Magnus; Gad, Sophie; Giraud, Sophie; Denoux, Yves; Yonneau, Laurent; Méjean, A.; Vasiliu, Viorel; Richard, Stéphane; MacKeigan, Jeffrey P.; Teh, Bin Tean; Furge, Kyle A.

doi:10.1186/1755-8794-3-59

Cited by 76 publications

(57 citation statements)

References 66 publications

(74 reference statements)

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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: 71%

“…Interestingly, it was shown recently that FLCN expression negatively correlates with PGC-1α activation in numerous tumors, such as those of the breast, cervix, colon, kidney, lung, lymph, ovary, pancreas, prostate, stomach, thyroid, and vulva (27). Specifically, the PGC-1α gene set and other OXPHOS gene sets correlated negatively with FLCN expression across all tumor types examined.…”

Section: Discussionmentioning

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: 71%

Section: Discussionmentioning

confidence: 99%

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

et al. 2014

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“…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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“…BHDS-related renal tumors are genetically distinct from other renal tumors including chromophobe RCC and oncocytoma. Additionally, increased expression of mitochondria-and oxidative phosphorylation-associated genes has been described in BHDS-derived renal tumors [54]. The mechanism leading to damage of the FLCN gene that leads to renal tumors remains unknown [55].…”

Section: Molecular Genetic Findingsmentioning

confidence: 99%

Review of renal tumors associated with Birt-Hogg-Dubé syndrome with focus on clinical and pathobiological aspects

Furuya¹,

Nagashima²,

Gotohda³

et al. 2014

pjp

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Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant inherited disorder characterized by clinical features of skin lesions, pulmonary lesions and renal tumor. The gene responsible for this syndrome is located on chromosome 17p11.2 and designated as FLCN. In this article, we review renal tumors associated with BHDS with a focus on clinical and pathobiological aspects. Renal tumors often occur multifocally or bilaterally in the imaging analyses or gross examination. Histological examination of renal tumors includes a variety of subtypes such as hybrid oncocytic tumor, chromophobe renal cell carcinoma (RCC), oncocytoma, clear cell RCC and papillary RCC. The histologic discordance in multiple tumors seems to be characteristic of this syndrome. Oncocytosis is observed histologically in about half of the cases. Several investigations have elucidated that folliculin may be involved in the mammalian target of rapamycin (mTOR) pathway recently. Renal tumors composed of clear cells may behave in an aggressive fashion. However, renal tumors including hybrid oncocytic tumor, chromophobe RCC and oncocytoma behave mostly in an indolent fashion.

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Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression

Cited by 76 publications

References 66 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

Review of renal tumors associated with Birt-Hogg-Dubé syndrome with focus on clinical and pathobiological aspects

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