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AN1 type zinc finger protein 3 ZFAND3 is part of a transcriptional complex that drives Glioblastoma invasion

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. New insight in molecular pathways underlying invasion to identify novel invasion-specific molecular targets are likely to improve treatment success and patient outcome. In the present study, we used a genome-wide interference screen to determine invasion-essential genes and identified the AN1/A20 zing finger domain containing protein 3 (ZFAND3) as a crucial driver of invasion in GBM. Using patient-derived cellular GBM models, we validated that loss of ZFAND3 dampens the invasive capacity of GBM, whereas ZFAND3 overexpression increases motility in GBM cells that were initially not invasive. At the mechanistic level, we demonstrate that ZFAND3 activity requires nuclear localization and integral zinc-finger domains. Using integrated transcriptomic and proteomic approaches coupled with reporter assays, we identify ZFAND3 as a novel functional member of a protein complex encompassing PUF60 to activate transcription and GBM cell invasion. Our findings indicate that ZFAND3 regulates the promoter of invasion-related genes such as COL6, FN1 and NRCAM through direct binding to GC rich regions. To harness the therapeutic potential of this transcriptional complex, further investigation in ZFAND3 function in GBM and related invasive cancer types is warranted.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Simone Niclou

PROVIDER: MSV000086247 | MassIVE | Thu Oct 08 02:03:00 BST 2020

SECONDARY ACCESSION(S): PXD021890

REPOSITORIES: MassIVE

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