MELK expression correlates with tumor mitotic activity but is not required for cancer growth

Giuliano, C. J., Lin, A., Smith, J. C., Palladino, A. C., Sheltzer, J. M. (February 2018) MELK expression correlates with tumor mitotic activity but is not required for cancer growth. Elife, 7. ISSN 2050-084x

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Abstract

The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (<xref ref-type="bibr" rid="bib34">Lin et al., 2017</xref>). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies.

Item Type:	Paper
Uncontrolled Keywords:	CRISPR/Cas9 biomarkers cancer biology cell cycle drug targets human mitotic kinase with Google Inc. The author has no financial interests to declare.
Subjects:	diseases & disorders > cancer Investigative techniques and equipment > CRISPR-Cas9 organs, tissues, organelles, cell types and functions > organelles, types and functions > mitosis
CSHL Authors:	Giuliano, Christopher Lin, Ann Sheltzer, Jason Palladino, Ann
Communities:	CSHL Cancer Center Program > Cancer Genetics CSHL labs > Sheltzer lab Northwell Health CSHL Cancer Center Program > Cancer Genetics and Genomics Program
Depositing User:	Matt Covey
Date:	8 February 2018
Date Deposited:	20 Feb 2018 20:39
Last Modified:	05 Nov 2020 19:27
PMCID:	PMC5805410
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/36079

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