2013 has been a busy year for BHD research, and with 2014 around the corner, it seems a good point to review the studies we’ve particularly enjoyed writing about, and to revisit emerging themes.
Early in the year, FLCN’s role in apoptosis and the cell cycle were a prominent theme on the blog. In January we wrote about the potential role of FNIP2 in driving MNU-induced apoptosis (Sano et al., 2013), while later in the year two separate studies showed that FLCN slows cell cycle progression; FLCN was found to inhibit cyclin D1 expression, and cell lines carrying FLCN mutations had a more rapid cell cycle profile than isogenic cells expressing FLCN (Kawai et al., 2013, Laviolette et al., 2013). Together this suggests that the FLCN-FNIP complexes act to both prevent cell overproliferation, and to promote apoptosis after DNA damage, providing new supporting evidence for FLCN being a tumour suppressor.
Two new animal models for BHD were published this year. In April, a C. elegans FLCN deletion mutant was reported to show increased longevity and thermoresistance than wildtype worms, due to increased HIF-signalling (Gharbi et al., 2013). In June, the first knock out fly model of BHD was published, showing that Drosophila homozygous for the FLCN deletion died as larvae due to defective TOR signalling (Liu et al., 2013) Both models suggest that FLCN’s role in mTOR signalling is conserved between species, and will aid BHD researchers find out more about FLCN’s function.
This year, several studies have discovered or refined links between FLCN and potential disease mechanisms.
Firstly, compound heterozygosity of FLCN and PTEN was shown to be the likely cause of oncocytic tumours specifically in the context of the cancer predisposition syndromes BHD and Cowden syndrome (Pradella et al., 2013). In April, the FLCN-FNIP1-FNIP2 complex was found to act as a developmental switch, allowing stem cells to exit pluripotency and become primed for differentiation, by controlling the nuclear localisation of the pluripotency transcription factor TFE3 (Betschinger et al., 2013).
Over the summer, it was suggested that BHD might be a ciliopathy as FLCN localises to motile cilia in a number of different cell types, and deletion of FLCN lead to cystic 3D spheroid formation and a reduction of β-catenin localisation in cilia (Luijten et al., 2013). More recently it was reported that the VHL gene’s tumour suppressor function is mediated by FLCN, and that loss of either gene induces autophagy (Bastola et al., 2013). Given the VHL gene’s central role in both familial and sporadic kidney cancers, this study suggests that FLCN dysregulation may also be a contributing factor in the development of non BHD-associated kidney cancers.
This autumn, the role of mTOR signalling and autophagy in BHD and kidney cancer has emerged as a prominent theme on the blog. In addition to the Bastola study, two independent studies were published showing that FLCN activates mTOR signalling via the Rag proteins at the cytosolic surface of lysosomes (Petit et al., 2013, Tsun et al., 2013). However, while Petit et al. suggested that FLCN activates mTOR function by acting as a GEF towards RagA and RagB, Tsun et al. suggest that FLCN acts as a GAP towards RagC and RagD. Thus, more research is required to resolve exactly how FLCN activates mTOR signalling at the lysosome.
Finally, several studies have identified potential druggable targets or treatments for BHD. Two studies have shown that inhibiting the SSH2 gene or treating cells with the chemotherapy Paclitaxel specifically induced apoptosis in FLCN-null cells, but not FLCN-expressing cells, suggesting potential avenues to treat BHD renal tumours (Lu et al., 2013, Zhang et al., 2013). In August, an encouraging study showed that researchers from Imperial College in London had successfully used gene therapy to reinstate FLCN function in FLCN-null cells (Wong and Harbottle, 2013), also suggesting that gene therapy may be used to treat BHD in the future.
These studies are just a few of many published in 2013, which has been a demonstrably fruitful year for BHD research. We at the BHD Foundation are very much looking forward to seeing how the field develops in 2014 and wish all our readers a very Happy New Year.
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Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, & Czyzyk-Krzeska MF (2013). Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy. PloS one, 8 (7) PMID: 23922894
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Betschinger J, Nichols J, Dietmann S, Corrin PD, Paddison PJ, & Smith A (2013). Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell, 153 (2), 335-47 PMID: 23582324
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Gharbi H, Fabretti F, Bharill P, Rinschen MM, Brinkkötter S, Frommolt P, Burst V, Schermer B, Benzing T, & Müller RU (2013). Loss of the Birt-Hogg-Dubé gene product folliculin induces longevity in a hypoxia-inducible factor-dependent manner. Aging cell, 12 (4), 593-603 PMID: 23566034
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Kawai A, Kobayashi T, & Hino O (2013). Folliculin regulates cyclin D1 expression through cis-acting elements in the 3′ untranslated region of cyclin D1 mRNA. International journal of oncology, 42 (5), 1597-604 PMID: 23525507
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Laviolette LA, Wilson J, Koller J, Neil C, Hulick P, Rejtar T, Karger B, Teh BT, & Iliopoulos O (2013). Human folliculin delays cell cycle progression through late S and G2/M-phases: effect of phosphorylation and tumor associated mutations. PloS one, 8 (7) PMID: 23874397
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Liu W, Chen Z, Ma Y, Wu X, Jin Y, & Hou S (2013). Genetic characterization of the Drosophila birt-hogg-dubé syndrome gene. PloS one, 8 (6) PMID: 23799055
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Lu X, Boora U, Seabra L, Rabai EM, Fenton J, Reiman A, Nagy Z, & Maher ER (2013). Knockdown of Slingshot 2 (SSH2) serine phosphatase induces Caspase3 activation in human carcinoma cell lines with the loss of the Birt-Hogg-Dubé tumour suppressor gene (FLCN). Oncogene PMID: 23416984
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Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala RK, Tee AR, Land SC, Giles RH, Coull BJ, & van Steensel MA (2013). Birt-Hogg-Dube syndrome is a novel ciliopathy. Human molecular genetics, 22 (21), 4383-97 PMID: 23784378
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Petit CS, Roczniak-Ferguson A, & Ferguson SM (2013). Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. The Journal of cell biology, 202 (7), 1107-22 PMID: 24081491
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Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, MacKay A, Reis-Filho JS, Seri M, Turchetti D, & Gasparre G (2013). Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. European journal of human genetics : EJHG, 21 (10), 1169-72 PMID: 23386036
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Sano S, Sakagami R, Sekiguchi M, & Hidaka M (2013). Stabilization of MAPO1 by specific binding with folliculin and AMP-activated protein kinase in O⁶-methylguanine-induced apoptosis. Biochemical and biophysical research communications, 430 (2), 810-5 PMID: 23201403
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Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, & Sabatini DM (2013). The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1. Molecular cell, 52 (4), 495-505 PMID: 24095279
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Wong SP, & Harbottle RP (2013). Genetic modification of dividing cells using episomally maintained S/MAR DNA vectors. Molecular therapy. Nucleic acids, 2 PMID: 23941867
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Zhang Q, Si S, Schoen S, Chen J, Jin XB, & Wu G (2013). Suppression of autophagy enhances preferential toxicity of paclitaxel to folliculin-deficient renal cancer cells. Journal of experimental & clinical cancer research : CR, 32 (1) PMID: 24305604
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.