A synthetic lethal screen identifies HDAC4 as a potential target in MELK overexpressing cancers

Author:

Zhou Lin1,Zheng Siqi1,Rosas Bringas Fernando R1ORCID,Bakker Bjorn1,Simon Judith E1,Bakker Petra L1,Kazemier Hinke G1,Schubert Michael1,Roorda Maurits2ORCID,van Vugt Marcel A T M2,Chang Michael1ORCID,Foijer Floris1ORCID

Affiliation:

1. European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, The Netherlands

2. Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, The Netherlands

Abstract

Abstract Maternal embryonic leucine zipper kinase (MELK) is frequently overexpressed in cancer, but the role of MELK in cancer is still poorly understood. MELK was shown to have roles in many cancer-associated processes including tumor growth, chemotherapy resistance, and tumor recurrence. To determine whether the frequent overexpression of MELK can be exploited in therapy, we performed a high-throughput screen using a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential when MELK is overexpressed. We identified two such genes: LAG2 and HDA3. LAG2 encodes an inhibitor of the Skp, Cullin, F-box containing (SCF) ubiquitin-ligase complex, while HDA3 encodes a subunit of the HDA1 histone deacetylase complex. We find that one of these synthetic lethal interactions is conserved in mammalian cells, as inhibition of a human homolog of HDA3 (Histone Deacetylase 4, HDAC4) is synthetically toxic in MELK overexpression cells. Altogether, our work identified a novel potential drug target for tumors that overexpress MELK.

Funder

Chinese Scholarship Council fellowship

UMCG Cancer Research Fund

CONACYT scholarship

Dutch Cancer Society

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology

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