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Investigation of the Folliculin (Flcn) Tumor Suppressor Gene in Energy Metabolism Ming Yan Department of Biochemistry Mcgill

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Investigation of the Folliculin (Flcn) Tumor Suppressor Gene in Energy Metabolism Ming Yan Department of Biochemistry Mcgill Investigation of the Folliculin (Flcn) tumor suppressor gene in energy metabolism Ming Yan Department of Biochemistry McGill University Montréal, Canada Dec., 2015 A thesis submitted to McGill University in partial fulfillment of the requirements for the degree of Doctor of Philosophy. © Ming Yan, 2015 ABSTRACT Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant hereditary disorder characterized by skin fibrofolliculomas, lung cyst, spontaneous pneumothorax and renal cell carcinoma (RCC). This condition is caused by germline mutations of folliculin (Flcn) gene, which encodes a 64-kDa protein named folliculin (FLCN). The AMP-actived protein kinase (AMPK) is a master regulator of cellular energy homeostasis. FLCN interacts with AMPK through FLCN-interacting proteins (FNIP1/2). Molecular function of FLCN and how FLCN interacts with AMPK in energy metabolism are largely unknown. We used mouse embryonic fibroblasts (MEFs) and adipose specific Flcn knockout mouse model to investigate the role of Flcn and its function associated with AMPK in energy metabolism. We found that loss of FLCN constitutively activates AMPK, which in turn leads to elevation in peroxisome proliferator-activated receptor gama coactivator 1 α (PGC-1α), which mediates mitochondrial biogenesis and increase reactive oxygen species (ROS) production. Elevated ROS induces hypoxia-inducible factor (HIF) transcriptional activity and drives Warburg metabolic reprogramming. These findings indicate that Flcn exert tumor suppressor activity by acting as a negative regulator of AMPK-dependent HIF activation and Warburg effect. To investigate the potential role of FLCN/AMPK/ PGC-1α in fat metabolism, we generated an adipose-specific Flcn knockout mouse model. Flcn KO mice exhibit elevated energy expenditure associated with increased O2 consumption, and are protected from diet-induced obesity. Importantly, loss of FLCN leads to increase in AMPK-dependent PGC-1 α and ERR α signaling, which are recognized as thermogenic and/or key regulators of mitochondrial biogenesis. Accordingly, several mitochondrial genes including uncoupling protein 1 (UCP1) are upregulated in Flcn KO white adipose tissue (WAT). As a consequence, the Flcn KO mice are more resistant to cold exposure associated with a higher UCP1 expression, which promotes fat burning by heat. Taken together, FLCN is a negative regulator of AMPK. Loss of Flcn results in AMPK dependent PGC-1 α activation, which 1) drives tumorigenic metabolic adaptation 1 by ROS induced HIF activity, 2) inhibits fat accumulation by increased FAO and UCP1 expression. 2 Résumé Le syndrôme Birt-Hogg-Dubé (BHD) est une maladie autosomale dominante héréditaire charactérisée par des troubles de la peau, des kystes pulmonaires, des pneumothorax spontanés et l'apparition de tumeurs rénales. Cette condition est causée par des mutations germinales dans le gène codant pour la protéine de 64 kDa nommée folliculine (FLCN). La protéine AMPK (AMP-activated protein kinase) est une clé de voute de l'homéostasie énergétique de la cellule. FLCN interagit avec AMPK par le biais de l'interaction avec les FNIP, les FLCN-interacting proteins. On ignore toujours le détail des fonctions moléculaires de FLCN, ainsi que de son impact sur le métabolisme cellulaire à travers son interaction avec AMPK. Dans le cadre des travaux présentés dans cette thèse, nous avons utilisé des fibroblastes embryonniques de souris (MEFs) et des souris avec une délétion ciblé du gène Flcn dans le tissus adipeux de façon à étudier le rôle de FLCN dans l'homéostasie du métabolisme énergétique. Nous avons découvert que la répression ou la délétion de FLCN entraine une activation constitutive d'AMPK qui promeut l'activité de PGC-1α (peroxisome proliferator-activated receptor gama coactivator 1α), menant à une biogénèse accrue des mitochondries et de la production d'espèce réactive d'oxygène (ROS). Cette augmentation de ROS active le facteur de transcription HIF afin de favoriser une reprogrammation du métabolisme vers la glycolyse aérobie (effet Warburg). Ces résultats démontrent que FLCN jouent le rôle de suppresseur de tumeur en réprimant l'activation d'HIF dépendante d'AMPK, bloquant ainsi les changements du métabolisme pro-tumoraux. De façon à étudier le rôle potentiel de la voie FLCN/AMPK/PGC-1α dans le métabolisme des adipocytes, nous avons généré un modèle de souris aillant une inactivation ciblée du gène Flcn au niveau des tissus adipeux. Dans ces expériences, les souris portant la délétion génétique démontraient une augmentation de leur métabolisme avec une plus grande consommation d'O2, leur conférant ainsi une protection contre l'obésité. Nous expliquons cette observation par le fait que la perte de FLCN entraîne une activation de la voie AMPK et de ces effecteurs PGC-1α et ERRα, qui sont reconnus comme des facteurs clés favorisant la biogénèse et l'activité des mitochondries. Ainsi, dans 3 les tissus adipeux des souris porteuses de la délétion, plusieurs gènes associés au métabolisme énergétique sont augmentés, notamment UCP1 (uncoupling protein 1). Par conséquent, les souris porteuses de la délétion Flcn démontrent une thermogène accrue lors de l'exposition au froid, puisque le tissu adipeux de ces souris est énergétiquement plus actif. En conclusion, FLCN est un régulateur négatif de la voie d'AMPK. Ainsi, la répression de FLCN hyperactive la voie d'AMPK et son effecteur PGC-1 α, ce qui entraîne: 1) une adaptation métabolique oncogénique dépendante de l'activité de HIF et 2) une inhibition de l'accumulation des lipides via une activation de leur oxydation. 4 TABLE OF CONTENTS ABSTRACT......................................................................................................................... 1 RÉSUMÉ............................................................................................................................. 3 TABLE OF CONTENTS..................................................................................................... 5 ACKNOWLEDGEMENTS ...............................................................................................10 LIST OF FIGURES ............................................................................................................11 LIST OF TABLES .............................................................................................................13 LIST OF ABBREVIATIONS ............................................................................................14 CONTRIBUTION OF AUTHORS.....................................................................................17 CHAPTER 1: .....................................................................................................................18 INTRODUCTION .............................................................................................................18 1.1 Birt-Hogg-Dubé syndrome.........................................................................................19 1.1.1 Epidemiology ....................................................................................................19 1.1.2 Birt-Hogg-Dubé disease clinical manifestations ...............................................21 1.1.3 BHD therapy ………………….........................................................................23 1.2 Folliculin gene...................................................................................................23 1.2.1 Identification of the FLCN gene .......................................................................23 1.2.2 FLCN mutations ...............................................................................................24 1.3 Folliculin and its interacting proteins................................................................25 1.3.1 FLCN protein....................................................................................................25 1.3.2 Folliculin-interacting proteins: FNIP1/ FNIP2/ AMPK complex.....................25 1.3.3 Other FLCN-interacting protein .......................................................................29 1.4 Folliculin associated signaling pathways .........................................................29 1.4.1 mTOR signaling................................................................................................29 1.4.2 HIF signaling.....................................................................................................30 5 1.4.3 Autophagy signaling.........................................................................................31 1.4.4 TGF-β signaling................................................................................................32 1.4.5 PGC1α signaling...............................................................................................33 1.4.6 FLCN loss drives AMPK-dependent cellular metabolism...............................35 1.5 OVERVIEW OF THE THESIS........................................................................38 CHAPTER 2: ....................................................................................................................40 The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation...................................................................................................................40 2.1 ABSTRACT.....................................................................................................41 2.2 INTRODUCTION............................................................................................42 2.3 RESULTS.........................................................................................................43
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