PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1

Alessandro Poli (), Fabrizio A. Pennacchio, Andrea Ghisleni, Mariagrazia Gennaro, Margaux Lecacheur, Paulina Nastały, Michele Crestani, Francesca M. Pramotton, Fabio Iannelli, Galina Beznusenko, Alexander A. Mironov, Valeria Panzetta, Sabato Fusco, Bhavwanti Sheth, Dimos Poulikakos, Aldo Ferrari, Nils Gauthier, Paolo A. Netti, Nullin Divecha and Paolo Maiuri ()
Additional contact information
Alessandro Poli: IFOM ETS - The AIRC Institute of Molecular Oncology
Fabrizio A. Pennacchio: IFOM ETS - The AIRC Institute of Molecular Oncology
Andrea Ghisleni: IFOM ETS - The AIRC Institute of Molecular Oncology
Mariagrazia Gennaro: IFOM ETS - The AIRC Institute of Molecular Oncology
Margaux Lecacheur: IFOM ETS - The AIRC Institute of Molecular Oncology
Paulina Nastały: University of Gdańsk and Medical University of Gdańsk
Michele Crestani: IFOM ETS - The AIRC Institute of Molecular Oncology
Francesca M. Pramotton: EMPA-Materials Science and Technology
Fabio Iannelli: IFOM ETS - The AIRC Institute of Molecular Oncology
Galina Beznusenko: IFOM ETS - The AIRC Institute of Molecular Oncology
Alexander A. Mironov: IFOM ETS - The AIRC Institute of Molecular Oncology
Valeria Panzetta: University of Naples Federico II
Sabato Fusco: University of Molise
Bhavwanti Sheth: University of Southampton
Dimos Poulikakos: Institute for Mechanical Systems, ETH
Aldo Ferrari: Institute for Mechanical Systems, ETH
Nils Gauthier: IFOM ETS - The AIRC Institute of Molecular Oncology
Paolo A. Netti: University of Naples Federico II
Nullin Divecha: University of Southampton
Paolo Maiuri: IFOM ETS - The AIRC Institute of Molecular Oncology

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Phosphatidylinositol-5-phosphate (PtdIns5P)−4-kinases (PIP4Ks) are stress-regulated phosphoinositide kinases able to phosphorylate PtdIns5P to PtdIns(4,5)P2. In cancer patients their expression is typically associated with bad prognosis. Among the three PIP4K isoforms expressed in mammalian cells, PIP4K2B is the one with more prominent nuclear localisation. Here, we unveil the role of PIP4K2B as a mechanoresponsive enzyme. PIP4K2B protein level strongly decreases in cells growing on soft substrates. Its direct silencing or pharmacological inhibition, mimicking cell response to softness, triggers a concomitant reduction of the epigenetic regulator UHRF1 and induces changes in nuclear polarity, nuclear envelope tension and chromatin compaction. This substantial rewiring of the nucleus mechanical state drives YAP cytoplasmic retention and impairment of its activity as transcriptional regulator, finally leading to defects in cell spreading and motility. Since YAP signalling is essential for initiation and growth of human malignancies, our data suggest that potential therapeutic approaches targeting PIP4K2B could be beneficial in the control of the altered mechanical properties of cancer cells.

Date: 2023
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DOI: 10.1038/s41467-023-37064-0

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