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Updated: Jun 23, 2026
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
A synthetic lethal screen identifies HDAC4 as a potential target in MELK overexpressing cancers
Lin Zhou1, Siqi Zheng1, Fernando R Rosas Bringas1
1European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, The Netherlands.
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.
Insights
Maternal embryonic leucine zipper kinase (MELK) is overexpressed in cancer. Researchers identified genes essential when MELK is overexpressed, revealing a potential new drug target for MELK-driven tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Maternal embryonic leucine zipper kinase (MELK) is frequently overexpressed in various cancers.
- The precise role of MELK in cancer progression, including tumor growth, drug resistance, and recurrence, remains incompletely understood.
- Understanding MELK's function is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To identify genes that become essential in the presence of MELK overexpression.
- To explore the therapeutic potential of targeting MELK-dependent vulnerabilities.
- To investigate conserved synthetic lethal interactions between MELK and other genes.
Main Methods:
- A high-throughput screen was conducted using a Saccharomyces cerevisiae mutant library.
- Genes whose functions were essential upon MELK overexpression were identified.
- Synthetic lethal interactions were validated in mammalian cells, focusing on homologs of identified yeast genes.
Main Results:
- Two genes, LAG2 and HDA3, were identified as essential when MELK is overexpressed.
- LAG2 inhibits the Skp, Cullin, F-box containing (SCF) ubiquitin-ligase complex.
- HDA3 is a subunit of the HDA1 histone deacetylase complex, and its human homolog, HDAC4, showed synthetic toxicity in MELK-overexpressing cells.
Conclusions:
- The study identified novel synthetic lethal interactions related to MELK overexpression.
- Inhibition of Histone Deacetylase 4 (HDAC4) presents a potential therapeutic strategy for cancers with high MELK levels.
- This research uncovers a promising new drug target for specific cancer types.
