論文

査読有り 国際誌
2020年2月19日

FLCN alteration drives metabolic reprogramming towards nucleotide synthesis and cyst formation in salivary gland.

Biochemical and biophysical research communications
  • Yasuhiro Isono
  • ,
  • Mitsuko Furuya
  • ,
  • Tatsu Kuwahara
  • ,
  • Daisuke Sano
  • ,
  • Kae Suzuki
  • ,
  • Ryosuke Jikuya
  • ,
  • Taku Mitome
  • ,
  • Shinji Otake
  • ,
  • Takashi Kawahara
  • ,
  • Yusuke Ito
  • ,
  • Kentaro Muraoka
  • ,
  • Noboru Nakaigawa
  • ,
  • Yayoi Kimura
  • ,
  • Masaya Baba
  • ,
  • Kiyotaka Nagahama
  • ,
  • Hiroyuki Takahata
  • ,
  • Ichiro Saito
  • ,
  • Laura S Schmidt
  • ,
  • W Marston Linehan
  • ,
  • Tatsuhiko Kodama
  • ,
  • Masahiro Yao
  • ,
  • Nobuhiko Oridate
  • ,
  • Hisashi Hasumi

522
4
開始ページ
931
終了ページ
938
記述言語
英語
掲載種別
DOI
10.1016/j.bbrc.2019.11.184

FLCN is a tumor suppressor gene which controls energy homeostasis through regulation of a variety of metabolic pathways including mitochondrial oxidative metabolism and autophagy. Birt-Hogg-Dubé (BHD) syndrome which is driven by germline alteration of the FLCN gene, predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas, pulmonary cysts and less frequently, salivary gland tumors. Here, we report metabolic roles for FLCN in the salivary gland as well as their clinical relevance. Screening of salivary glands of BHD patients using ultrasonography demonstrated increased cyst formation in the salivary gland. Salivary gland tumors that developed in BHD patients exhibited an upregulated mTOR-S6R pathway as well as increased GPNMB expression, which are characteristics of FLCN-deficient cells. Salivary gland-targeted Flcn knockout mice developed cytoplasmic clear cell formation in ductal cells with increased mitochondrial biogenesis, upregulated mTOR-S6K pathway, upregulated TFE3-GPNMB axis and upregulated lipid metabolism. Proteomic and metabolite analysis using LC/MS and GC/MS revealed that Flcn inactivation in salivary gland triggers metabolic reprogramming towards the pentose phosphate pathway which consequently upregulates nucleotide synthesis and redox regulation, further supporting that Flcn controls metabolic homeostasis in salivary gland. These data uncover important roles for FLCN in salivary gland; metabolic reprogramming under FLCN deficiency might increase nucleotide production which may feed FLCN-deficient salivary gland cells to trigger tumor initiation and progression, providing mechanistic insight into salivary gland tumorigenesis as well as a foundation for development of novel therapeutics for salivary gland tumors.

リンク情報
DOI
https://doi.org/10.1016/j.bbrc.2019.11.184
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31806376

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