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

Birt-Hogg-Dube (BHD) syndrome patients are uniquely susceptible to all renal tumour subtypes. The underlying mechanism of carcinogenesis is unclear. To study cancer development in BHD, we used human proximal kidney (HK2) cells with short-term and long-term folliculin (FLCN) knockdown. HK2 cells lacking FLCN had an altered transcriptome profile with cell cycle control gene enrichment. G1/S cell cycle checkpoint signaling was compromised with heightened protein levels of cyclin D1 (CCND1) and hyperphosphorylation of retinoblastoma 1 (RB1). Taken together with our proteomic work, our findings indicate that long-term FLCN loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer. RNAseq profiling of human kidney proximal tubule cells (HK2) with short-term (< 30 passages) and long-term (>120 passages) knockdown of FLCN, compared to their wild-type controls.