ArticleBiochemical and biophysical research communications2020
FLCN alteration drives metabolic reprogramming towards nucleotide synthesis and cyst formation in salivary gland.
Article in Biochemical and biophysical research communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
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Who cites it
7 citing papers in PubMed, 1 synthesis or guideline pooled it, 6 citations in OpenAlex.
- A Possible Association of Salivary Gland Tumors and Oral Lesions with Birt-Hogg-Dube Syndrome: A Systematic Review.Head and neck pathology · 2024Pooled it
- Establishment of Salivary Gland Tumors Arising in Salivary Gland-Specific EWSR1::ATF1 Transgenic Mice.Head & neck · 2026Article
- Parotid Oncocytomas Express the Glycoprotein Non-metastatic Melanoma Protein B (GPNMB): A Potential Link with Birt-Hogg-Dubé Syndrome.Head and neck pathology · 2026Article
- A case report of ectopic salivary gland tissue in the tongue base.Radiology case reports · 2023Article
- Oncocytic carcinoma of the parotid gland as a manifestation of Birt-Hogg-Dube syndrome.Radiology case reports · 2023Article
- Melatonin Signaling Pathways Implicated in Metabolic Processes in Human Granulosa Cells (KGN).International journal of molecular sciences · 2022Article
- Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways.Frontiers in cell and developmental biology · 2021Review
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Authors and funding
23 authors at 8 institutions in 2 countries.
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Abstract
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.
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