Characterizing the tumor suppressor activity of FLCN in Birt-Hogg-Dubé syndrome through transcriptiomic and proteomic analysis

Jones, Rachel-Ann, Dunlop, Elaine ORCID: https://orcid.org/0000-0002-9209-7561, Champion, Jesse, Doubleday, Peter F., Claessens, Tijs, Jalali, Zahra, Seifan, Sara, Perry, Iain, Giles, Peter ORCID: https://orcid.org/0000-0003-3143-6854, Harrison, Oliver, Coull, Barry J., Houweling, Arjan C., Pause, Arnim, Ballif, Bryan A. and Tee, Andrew ORCID: https://orcid.org/0000-0002-5577-4631 2025. Characterizing the tumor suppressor activity of FLCN in Birt-Hogg-Dubé syndrome through transcriptiomic and proteomic analysis. Oncogene 10.1038/s41388-025-03325-z

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Abstract

Birt-Hogg-Dubé syndrome (BHD) patients are uniquely susceptible to all renal tumor subtypes. However, the underlying mechanism of carcinogenesis is unclear. To study cancer development in BHD, we used human proximal kidney (HK2) cells and found that long-term folliculin (FLCN) knockdown was required to increase the tumorigenic potential of these cells, as evidenced by the formation of larger spheroids under nonadherent conditions. Transcriptomic and proteomic analyses revealed links between the FLCN, cell cycle control and DNA damage response (DDR) machinery. In addition, HK2 cells lacking FLCN had an altered transcriptome profile and enriched cell cycle control genes. G1/S cell cycle checkpoint signaling was compromised by increased protein levels of cyclin D1 (CCND1) and hyperphosphorylation of retinoblastoma 1 (RB1). A FLCN interactome screen revealed that FLCN binds to DNA-dependent protein kinase (DNA-PK). This novel interaction was reversed in an irradiation-responsive manner. Knockdown of FLCN in HK2 cells caused a marked increase in γH2AX and RB1 phosphorylation. The levels of both CCND1 and phosphorylated RB1 remained high during DNA damage, which was associated with defective cell cycle control caused by FLCN knockdown. Furthermore, Flcn-knockdown C. elegans were defective in cell cycle arrest caused by DNA damage. This work revealed that long-term FLCN loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer.

Item Type:	Article
Date Type:	Publication
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0950-9232
Date of First Compliant Deposit:	11 March 2025
Date of Acceptance:	21 February 2025
Last Modified:	04 Apr 2025 14:48
URI:	https://orca.cardiff.ac.uk/id/eprint/176807

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