AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion

Anne Schuster1, Eliane Klein1, Virginie Neirinckx1, Arnon Møldrup Knudsen2,3, Carina Fabian1,4, Ann-Christin Hau1, Monika Dieterle1, Anais Oudin1, Petr V Nazarov5, Anna Golebiewska1, Arnaud Muller5, Daniel Perez-Hernandez5, Sophie Rodius5, Gunnar Dittmar5, Rolf Bjerkvig1,4, Christel Herold-Mende6, Barbara Klink7,8, Bjarne Winther Kristensen2,3, Simone P Niclou9,10

  1. NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
  2. Department of Pathology, Odense University Hospital, Odense, Denmark.
  3. Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
  4. Department of Biomedicine, University of Bergen, Bergen, Norway.
  5. Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg.
  6. Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
  7. National Center of Genetics, Laboratoire National de Santé, Dudelange, Luxembourg.
  8. Functional Tumor Genetics, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
  9. NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg. simone.niclou@lih.lu.
  10. Department of Biomedicine, University of Bergen, Bergen, Norway. simone.niclou@lih.lu.

Abstract

The infiltrative nature of Glioblastoma (GBM), the most aggressive primary brain tumor, critically prevents complete surgical resection and masks tumor cells behind the blood brain barrier reducing the efficacy of systemic treatment. Here, we use a genome-wide interference screen to determine invasion-essential genes and identify the AN1/A20 zinc finger domain containing protein 3 (ZFAND3) as a crucial driver of GBM invasion. Using patient-derived cellular models, we show that loss of ZFAND3 hampers the invasive capacity of GBM, whereas ZFAND3 overexpression increases motility in cells that were initially not invasive. At the mechanistic level, we find that ZFAND3 activity requires nuclear localization and integral zinc-finger domains. Our findings indicate that ZFAND3 acts within a nuclear protein complex to activate gene transcription and regulates the promoter of invasion-related genes such as COL6A2, FN1, and NRCAM. Further investigation in ZFAND3 function in GBM and other invasive cancers is warranted.

Presented By Virginie Neirinckx

Genomics, Medicine, NeuroscienceNicholas Liao2020-12 (Dec)