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 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.
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
Prabhat
P
Bastola
Yiwen
Y
Stratton
Emily
E
Kellner
Olga
O
Mikhaylova
Ying
Y
Yi
Maureen A
MA
Sartor
Mario
M
Medvedovic
Jacek
J
Biesiada
Jarek
J
Meller
Maria F
MF
Czyzyk-Krzeska
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D004970:Estrone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
D004970:Estrone; D051794:Von Hippel-Lindau Tumor Suppressor Protein