@misc{10481/106487,
year = {2025},
month = {9},
url = {https://hdl.handle.net/10481/106487},
abstract = {Lung cancer is the leading cause of cancer-related deaths worldwide, with lung squamous cell carcinoma (LUSC)
lacking effective targeted therapies. Recent studies have identified Plakophilin-1 (PKP1) as one of the most
differentially overexpressed genes in LUSC. This is particularly intriguing given that PKP1 is primarily known as
a desmosomal component involved in cell adhesion, typically regarded as a tumor suppressor. To elucidate its
biological role, we performed a genome-wide CRISPR knockout screening in PKP1-deficient models, revealing
a strong dependence on mitochondrial metabolism. Metabolic assays further demonstrated that PKP1 loss
significantly disrupts both mitochondrial function and glycolytic activity. In contrast, cells expressing PKP1 display a
metabolically hyperactive phenotype, characterized by elevated oxygen consumption rate (OCR) and extracellular
acidification rate (ECAR). Building on these findings, we found that PKP1 depletion selectively reduces platelet-type
phosphofructokinase (PFKP) levels, a key rate-limiting enzyme in glycolysis, by enhancing its ubiquitination and
subsequent degradation. Functional rescue experiments confirmed that PFKP mediates the proliferative role of
PKP1. These findings suggest that PKP1 overexpression in LUSC promotes a hyperactive metabolic state binding to
TRIM21 and preventing PFKP degradation, facilitating tumor progression. These effects were consistently observed
across multiple LUSC cell lines, underscoring the robustness of the mechanism. These findings highlight a potential
therapeutic vulnerability in LUSC metabolic regulation.},
organization = {Consejería de Salud y Consumo de la Junta
de Andalucía (grants PI-0228-2024, PI-0203-2022 and PIGE-0213-2020)},
organization = {Ministry of Science and Innovation of Spain (grants PID2021-126111OB-I00
and PID2024-159252OB-I00)},
organization = {University of Granada (grants B-CTS480-UGR20, C-EXP-051-UGR23 and C-CTS-149-UGR23)},
organization = {Spanish
Association for Cancer Research(LABORATORY-AECC-2018)},
organization = {Spanish Ministry of Education and Professional Training (FPU17/05124)},
organization = {Spanish Ministry of Universities - European Molecular Biology
Organization (FPU17/01258)},
organization = {Spanish Ministry of Universities - European Union Next Generation (IG 2024 - ID. 30924 project)},
publisher = {Springer},
keywords = {Plakophilin-1},
keywords = {Phosphofructokinase},
keywords = {TRIM21},
title = {PKP1 promotes lung cancer by modulating energy metabolism through stabilization of PFKP},
doi = {10.1186/s40364-025-00815-w},
author = {Ritoré Salazar, Félix and Arenas, Alberto and Matia González, Ana María and Zaza, Alessandra and Aagaard Thomsen, Emil and Bruun Rovsing, Anne and Giehm Mikkelsen, Jacob and Noguera, Nelida Ines and Medina Vico, Pedro Pablo},
}