PCDHGC3 silencing promotes clear cell renal cell carcinoma metastasis via mTOR/HIF2α activation, lipid metabolism rewiring, and ferroptosis evasion
Year: 2026
Type: article
Abstract: Clear cell renal cell carcinoma (ccRCC) remains a major clinical challenge due to its high metastatic potential and limited treatment options. Here, we identified PCDHGC3 as a critical tumor suppressor, whose downregulation drives ccRCC aggressiveness. Through integrated molecular analyses, we demonstrated that PCDHGC3 deficiency promoted proliferation, epithelial-to-mesenchymal transition, and metastatic dissemination in both in vitro and in vivo models. Mechanistically, PCDHGC3 knockdown activated mTOR signaling, leading to aberrant HIF2α stabilization, a well-established oncogenic driver in ccRCC. Upstream of this cascade, PCDHGC3 loss was associated with increased focal adhesion kinase (FAK) activation, providing a context-specific link between membrane signaling and mTOR-HIF2α pathway activation. Pharmacological inhibition of mTOR suppresses HIF2α activity and targeting either pathway partially rescues the hyperproliferative and pro-metastatic phenotype of PCDHGC3-deficient cells. Proteomic analysis further revealed that PCDHGC3 loss reprograms lipid metabolism, particularly by increasing fatty acid synthesis and lipid droplet (LD) formation. We identify PLIN2, a HIF2α-regulated gene, as a key mediator of LD stability in PCDHGC3-knockdown cells. By sequestering lipids into LDs, PLIN2 protects against ferroptosis, an iron-dependent form of cell death triggered by lipid peroxidation. Notably, PLIN2 knockdown increases ferroptotic sensitivity, revealing LD biogenesis as a major survival mechanism in PCDHGC3-deficient ccRCC. Together, these findings establish a PCDHGC3-mTOR-HIF2α-PLIN2 axis that underlines both metastatic behavior and ferroptosis evasion. Clinically, this suggests that combining ferroptosis inducers with mTOR or HIF2α inhibitors-and potentially targeting PLIN2-could provide a multifaceted therapeutic strategy against advanced ccRCC. By elucidating the tumor-suppressive role of PCDHGC3, this study expands our understanding of clustered PCDH biology and offers novel insights for ccRCC management.
Source: Cell Death and Disease
Authors: Lucía Celada, Tamara Cubiella, Jaime San-Juan-Guardado, Álvaro Suárez-Priede, Nerea Gómez-Suárez, Laura Salerno, Eduardo Murias, Marina Da Silva Torres, Joshua A. Weiner, Helena Herrada-Manchón, M. Alejandro Fernández, María-Dolores Chiara
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,990
Awards: G1105844351, G1175115578, G1341303, G1622782223, G210041235, G2262748287, G2601397997, G300979063, G34346518, G3480869486, G3681454997, PROTOCADHERINAS EN PARAGANGLIOMAS Y FEOCROMOCITOMAS: SU PAPEL COMO BIOMARCADORES PREDICTIVOS Y PRONÓSTICOS DE ENFERMEDAD METASTÁSICA Y COMO DIANAS TERAPÉUTICAS, G3986013493, G4042783231, G410571670, G425668148, G451917667, G4526231891, G464105488, G491712853, G5080475149, G5195188938, G5404395142, G5539308778, G5635532810, G5967599077, G624877701, G7084143925, G7805626310, G7863371703, G8497050386, G929308097
OpenAlex ID: W7140405193