Enigmatic MELK: The controversy surrounding its complex role in cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Maternal embryonic leucine zipper kinase (MELK) is a Ser/Thr protein kinase investigated as a cancer therapeutic target since 2005.
• Elevated MELK expression is observed in various cancer cells and tissues compared to normal counterparts.
• Previous studies indicated MELK depletion via RNA interference (RNAi) and pharmacological inhibition impair cancer cell proliferation, including triple-negative breast cancer (TNBC).

Purpose of the Study:

• To review and analyze the conflicting evidence regarding the essentiality of MELK in cancer proliferation.
• To discuss the discrepancies observed between different methodologies (RNAi, pharmacological inhibition, CRISPR/Cas9) in assessing MELK's role.
• To highlight the need for further research into MELK's functions in cancer.

Main Methods:

• Review of existing literature on MELK's role in cancer.
• Analysis of studies employing RNAi-mediated MELK depletion.
• Examination of research utilizing pharmacological MELK inhibitors (e.g., OTS167, NVS-MELK8a).
• Inclusion of studies using CRISPR/Cas9 gene editing to delete MELK.

Main Results:

• RNAi and pharmacological inhibition suggest MELK is essential for cancer cell proliferation, with rescued growth upon reintroduction of wild-type MELK.
• CRISPR/Cas9-mediated MELK deletion showed no impact on the proliferation of TNBC and other cancer cell lines.
• Discrepancies in growth effects observed across different methodologies remain unexplained.

Conclusions:

• The essentiality of MELK in cancer proliferation is controversial and requires further investigation.
• Mechanisms underlying the conflicting results from RNAi, pharmacological inhibition, and CRISPR/Cas9 deletion need clarification.
• Continued research is crucial to fully elucidate the functions of MELK in cancer biology.