The maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer

Abstract

Loss of cell cycle control is a prerequisite for cancer onset and progression. In prostate cancer, increased activity of cell cycle genes has been associated with prognostic parameters such as biochemical relapse and survival. The identification of novel oncogenic and druggable targets in patient subgroups with poor prognosis may help to develop targeted therapy approaches. We analyzed prostate cancer and corresponding benign tissues (n = 98) using microarrays. The comparison of high- and low-grade tumors (Gleason score ≥ 4 + 3 vs. ≤ 3 + 4) revealed 144 differentially expressed genes (p < 0.05). Out of these, 15 genes were involved in the cell cycle process. The gene maternal embryonic leucine zipper kinase (MELK) was identified to be highly correlated with cell cycle genes like UBE2C, TOP2A, CCNB2, and AURKB. Increased MELK gene expression in high-risk prostate cancer was validated by qPCR in an independent patient cohort (p < 0.005, n = 79). Immunohistochemistry analysis using a tissue microarray (n = 94) revealed increased MELK protein expression in prostate cancer tissues of high Gleason scores. RNAi-based inhibition of MELK in PC3 and LNCaP cells suggested putative function in chromatin modification, embryonic development and cell migration. The concerted inhibition of MELK and other cell cycle targets by the antibiotic siomycin A strongly impaired cell viability of prostate cancer cells, and may point to a novel therapy approach for a subset of high-risk prostate cancer patients.

Maternal Embryonic Leucine Zipper Kinase: Key Kinase for Stem Cell Phenotype in Glioma and Other Cancers

“…The latest genome-wide gene sequencing analyses, made available by The Cancer Genome Atlas (National Institutes of Health; cancergenome.nih.gov), indicate that MELK seems to be overexpressed but not mutated in cancers. Perhaps complicating matters further, studies of MELK signaling in normal cells demonstrate a large and seemingly disjointed set of biological substrates whose activation leads to diverse cellular processes such as cell cycle progression and growth, cell migration, and DNA damage repair(2, 4, 14–17). Therefore, a small molecule compound that selectively inhibits MELK kinase activity may risk unwanted off-target effects in both normal and cancer cells.…”

“…Siomycin A treatment prevented mitotic entry and arrested treated cells in the G2/M transition, a phenotype that has been previously observed after siRNA-mediated MELK silencing. Another study by Kuner exhibited that Siomycin A treatment also induces mitotic cell cycle arrest in a prostate cancer cell line(4). …”

“…Thus far, significantly higher levels of MELK have been demonstrated in human cancers of the colon, breast, ovaries, pancreas, prostate and brain (glioblastoma; GBM) compared to normal cells(3, 4). Notably, a large-scale meta-analysis of microarray data identified MELK as a consistently expressed gene in the transcriptional profiles of undifferentiated cancers(5).…”

“…Notably, a large-scale meta-analysis of microarray data identified MELK as a consistently expressed gene in the transcriptional profiles of undifferentiated cancers(5). Indeed, studies have illustrated a correlation between MELK expression and tumor malignancy grade for astrocytoma, breast cancer, and prostate cancer, as well as radiation and chemoresistance in colorectal cancer(4, 6–8). In addition, MELK expression is inversely correlated with survival periods of patients with multiple cancer types(9, 10).…”

MELK inhibitor, novel molecular targeted therapeutics for human cancer stem cells

“…3,4 MELK is activated by autophosphorylation, and once it is activated, it then phosphorylates several substrates, such as a pro-apoptotic molecule Bcl-G and a cell cycle protein CDC25. 1,5 In addition, we and others have reported that MELK induces expression of oct3/4, a well-known a stem cell marker.…”