Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy

Von Hippel-Lindau tumor suppressor (VHL) is lost in the majority of clear cell renal cell carcinomas (ccRCC). Folliculin (FLCN) is a tumor suppressor whose function is lost in Birt-Hogg-Dubé syndrome (BHD), a disorder characterized by renal cancer of multiple histological types including clear cell...

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Published in:	PloS one 2013-07, Vol.8 (7), p.e70030-e70030
Main Authors:	Bastola, Prabhat, Stratton, Yiwen, Kellner, Emily, Mikhaylova, Olga, Yi, Ying, Sartor, Maureen A, Medvedovic, Mario, Biesiada, Jacek, Meller, Jarek, Czyzyk-Krzeska, Maria F
Format:	Article
Language:	eng
Subjects:	Allografts Animals Autophagy Autophagy - genetics Autophagy - physiology Biology Biotechnology Blotting, Western Cancer Cell death Clear cell-type renal cell carcinoma Crosstalk Environmental health Estrone - genetics Estrone - metabolism Gene expression Genes Hospitals Humans Hypoxia In Vitro Techniques Informatics Kidney cancer Kidney Neoplasms - genetics Kidney Neoplasms - metabolism Kidney transplantation Kinases Mathematics Medicine Metabolism Mice Mice, Nude MicroRNAs mRNA Neoplasia Phagocytosis Phosphatase Phosphorylation Pneumothorax Proteins Reverse Transcriptase Polymerase Chain Reaction RNA RNA polymerase Suppressors Syngeneic grafts Tumor cell lines Tumor suppressor genes Tumors VHL protein Von Hippel-Lindau Tumor Suppressor Protein - genetics Von Hippel-Lindau Tumor Suppressor Protein - metabolism Xenografts
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Summary:	Von Hippel-Lindau tumor suppressor (VHL) is lost in the majority of clear cell renal cell carcinomas (ccRCC). Folliculin (FLCN) is a tumor suppressor whose function is lost in Birt-Hogg-Dubé syndrome (BHD), a disorder characterized by renal cancer of multiple histological types including clear cell carcinoma, cutaneous fibrofolliculoma, and pneumothorax. Here we explored whether there is connection between VHL and FLCN in clear cell renal carcinoma cell lines and tumors. We demonstrate that VHL regulates expression of FLCN at the mRNA and protein levels in RCC cell lines, and that FLCN protein expression is decreased in human ccRCC tumors with VHL loss, as compared with matched normal kidney tissue. Knockdown of FLCN results in increased formation of tumors by RCC cells with wild-type VHL in orthotopic xenografts in nude mice, an indication that FLCN plays a role in the tumor-suppressing activity of VHL. Interestingly, FLCN, similarly to VHL, is necessary for the activity of LC3C-mediated autophagic program that we have previously characterized as contributing to the tumor suppressing activity of VHL. The results show the existence of functional crosstalk between two major tumor suppressors in renal cancer, VHL and FLCN, converging on regulation of autophagy.
ISSN:	1932-6203 1932-6203