Ramirez Reyes et al., recently provided an in-depth review of the functions of folliculin (FLCN). We previously published a blog piece based on this review discussing the role FLCN plays in the mTOR signalling pathway. Following on from this, we now focus on other pathways in which FLCN is involved and discuss the relevance to Birt-Hogg-Dubé Syndrome (BHD).

FLCN and RNA

FLCN has been identified as a negative regulator of ribosomal RNA synthesis and thus loss of FLCN can lead to an increase in translation through increased levels of ribosomes which are required for the hyperproliferative state of cancer cells. FLCN has also been linked to the upregulation of two microRNAs in cystic lesions of primary spontaneous pneumothorax in BHD patients. One of these has been shown to induce apoptosis, and the other is involved in mesenchymal to epithelial transition in lung fibroblasts which may be able to at least partly explain the development of lung lesions found in BHD.

FLCN and EGFR Signalling

A role for FLCN in epidermal growth factor receptor (EGFR) signalling has been demonstrated. Cell growth and mechanisms preventing apoptosis, which are hallmarks of cancer, are examples of events that occur downstream of EGFR signalling. Loss of FLCN in BHD-derived kidney tumours has been shown to enhance EGFR activation and therefore could lead to the hallmarks of cancer described.

FLCN and the Cell Cycle

Loss of FLCN leads to acceleration of progression through the G2/M phase of the cell cycle which results in increased cell proliferation. The mechanism by which FLCN controls this is unknown, but it has been hypothesised that it may be through the regulation of the oncogene cyclin D1. It is well established that activation of mTORC1 leads to an increase in cyclin D1 expression which may contribute to BHD-related tumorigenesis.

FLCN and Autophagy

Autophagy is the process by which cellular molecules are broken down and recycled to provide energy and the building blocks to maintain cellular homeostasis under conditions of stress or starvation. It has been reported that loss of FLCN in cells leads to AMPK-mediated induction of autophagy. This results in an inhibition of apoptosis and increased ATP levels which may confer an energetic advantage in tumours lacking FLCN which would support tumour progression under conditions of stress.

FLCN and Glycogen Metabolism

There is increasing evidence of a key role for glycogen in carcinogenesis and accumulation of glycogen has been observed in many cancer types, including renal tumours from BHD patients. A loss of FLCN has been shown to increase the expression of genes involved in glycogen synthesis. Breakdown of glycogen is also a driver of cancer cell proliferation and survival in models of glioblastoma, breast cancer and colon cancer and has shown to be important in the first steps of metastasis.

The role FLCN plays in cells is exceptionally complex and it not yet fully understood. It is complicated further by conflicting evidence in the literature of what FLCN does depending on the model used. Development of better models to study FLCN in the context of BHD would enable a more precise understanding of how a lack of FLCN contributes to the symptoms observed in BHD. This includes models for all the manifestations of BHD (skin, kidney and lung), better platforms for testing drugs on a large scale, inclusion of computational analysis to look at networks rather than single proteins or pathways. Without this deep knowledge of FLCN biology, development of new therapies is extremely difficult, which is why the BHD Foundation and Myrovlytis Trust are committed to funding research to develop these models so that they can be used to inform the development of treatments for BHD.

References

1.        Reyes JMJR, Cuesta R, Pause A. Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways. Front Cell Dev Biol. 2021;