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<p>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 (<i>FLCN</i>) 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 <i>FLCN</i> had an altered transcriptome profile and enriched cell cycle control genes. G<sub>1</sub>/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 <i>FLCN</i> 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 <i>FLCN</i> knockdown. Furthermore, <i>Flcn</i>-knockdown <i>C. elegans</i> were defective in cell cycle arrest caused by DNA damage. This work revealed that long-term <i>FLCN</i> loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月25日

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  • Rachel-Ann Jones,
  • Elaine A. Dunlop,
  • Jesse D. Champion,
  • Peter F. Doubleday,
  • Tijs Claessens,
  • Zahra Jalali,
  • Sara Seifan,
  • Iain A. Perry,
  • Peter Giles,
  • Oliver Harrison,
  • Barry J. Coull,
  • Arjan C. Houweling,
  • Arnim Pause,
  • Bryan A. Ballif,
  • Andrew R. Tee

摘要

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.