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ZNF750 represses breast cancer invasion via epigenetic control of prometastatic genes

Oncogene volume 39, pages 4331–4343 (2020)Cite this article

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Abstract

Breast cancer is the second leading cause of cancer-related deaths among women, largely due to the progression of a significant fraction of primary tumours to the metastatic stage. Here, we show that zinc-finger protein 750 (ZNF750) opposes the migration and invasion of breast cancer cells by repressing a prometastatic transcriptional programme, which includes genes involved in focal adhesion and extracellular matrix interactions, such as LAMB3 and CTNNAL1. Mechanistically, ZNF750 recruits the epigenetic modifiers KDM1A and HDAC1 to the promoter regions of LAMB3 and CTNNAL1, influencing histone marks and transactivating these genomic sites. Gene expression analysis in cancer patient datasets indicated that ZNF750 and its targets were negative prognostic factors in breast cancer. Together, our findings shed light on the molecular mechanism by which ZNF750 regulates cell migration and invasion, suggesting a role in breast cancer metastasis.

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Fig. 1: ZNF750 genetic alterations in breast cancer.
Fig. 2: ZNF750 regulates migration and invasion in breast cancer cells.
Fig. 3: ZNF750 regulates the WNT and focal adhesion pathways.
Fig. 4: ZNF750 inhibits breast cancer cell migration by repressing LAMB3 and CTNNAL1 expression.
Fig. 5: ZNF750 recruits KDM1A and HDAC1 to the promoters of the target genes.

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Acknowledgements

We would like to thank Dr Annalisa Conti for helpful comments and suggestions and K. Dudek and C. Jones for assistance in gene microarray analysis. This work has been supported by the Medical Research Council (to GM) UK, the Associazione Italiana per la Ricerca contro il Cancro (AIRC) (to GM; IG#20473 (2018–2022)), the AIRC (to EC; IG#22206 (2019–2023)), the AIRC (Start-Up to IA; ID 23219), the Ministero Salute, IDI-IRCCS (RC to EC), and the Italian Ministry of Foreign Affairs and International Cooperation (to EC). The work has also been supported by Regione Lazio through the LazioInnova Progetto Gruppo di Ricerca n 85-2017-14986 (to GM).

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  1. Matteo Cassandri

    Present address: Department of Oncohematology, Bambino Gesu’ Children’s Hospital, 00146, Rome, Italy

Authors and Affiliations

  1. Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133, Rome, Italy

    Matteo Cassandri, Alessio Butera, Ivano Amelio, Anna Maria Lena, Manuela Montanaro, Alessandro Mauriello, Lucia Anemona, Eleonora Candi, Massimiliano Agostini & Gerry Melino

  2. Department of Pathology, MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

    Ivano Amelio, Richard A. Knight & Gerry Melino

  3. IDI-IRCCS, via Monti di Creta, 106, 00166, Rome, Italy

    Eleonora Candi

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Cassandri, M., Butera, A., Amelio, I. et al. ZNF750 represses breast cancer invasion via epigenetic control of prometastatic genes. Oncogene 39, 4331–4343 (2020). https://doi.org/10.1038/s41388-020-1277-5

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