2. Academic Validation
  3. PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1

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

  • Nat Commun. 2023 Mar 14;14(1):1432. doi: 10.1038/s41467-023-37064-0.
Alessandro Poli 1,  Fabrizio A Pennacchio 2,  Andrea Ghisleni 2,  Mariagrazia di Gennaro 2,  Margaux Lecacheur 2,  Paulina Nastały 3,  Michele Crestani 2,  Francesca M Pramotton 4 5,  Fabio Iannelli 2,  Galina Beznusenko 2,  Alexander A Mironov 2,  Valeria Panzetta 6 7 8,  Sabato Fusco 9,  Bhavwanti Sheth 10,  Dimos Poulikakos 5,  Aldo Ferrari 5,  Nils Gauthier 2,  Paolo A Netti 6 7 8,  Nullin Divecha 10,  Paolo Maiuri 11 12
Affiliations

Affiliations

  • 1 IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy. allen2315@gmail.com.
  • 2 IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.
  • 3 Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdansk, Poland.
  • 4 EMPA-Materials Science and Technology, Dubenforf, Switzerland.
  • 5 Institute for Mechanical Systems, ETH, Zurich, Switzerland.
  • 6 Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Naples, Italy.
  • 7 Centro di Ricerca Interdipartimentale sui Biomateriali CRIB, University of Naples Federico II, Naples, Italy.
  • 8 Istituto Italiano di Tecnologia, IIT@CRIB, Naples, Italy.
  • 9 Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy.
  • 10 Inositide Laboratory, School of Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.
  • 11 IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy. paolo.maiuri@unina.it.
  • 12 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. paolo.maiuri@unina.it.
PMID: 36918565 DOI: 10.1038/s41467-023-37064-0
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.

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