MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

Abstract

Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stemlike cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK-or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stemlike cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients.Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma.Mol Cancer Res; 15(9); 1275-86. Ó2017 AACR.

Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma

“…Indeed, in breast cancer, another small-molecule inhibitor MELK-T1 has been shown to inhibit MELK autophosphorylation, leading to proteasomal degradation (32). In medulloblastoma MELK directly binds and phosphorylates EZH2 (33). Although MYCN has been shown to regulate EZH2 (34,35), significant correlations between MYCN and EZH2 expression in the neuroblastoma cell lines we analyzed were not detected.…”

Maternal embryonic leucine zipper kinase: A novel biomarker and a potential therapeutic target of cervical cancer

“…Kohler et al found that the use of MELK inhibitor OTSSP167 can induce G2/M cell cycle arrest, inhibit proliferation and colony formation, and induce apoptosis of HGSOC cell lines. Another two studies reported that MELK expression is associated with tumor cell mitosis and promotes tumor cell proliferation . MELK also plays an important role in the P53‐P21 apoptotic pathway .…”

Overexpression of PP1–NIPP1 limits the capacity of cells to repair DNA double-strand breaks

“…However, NIPP1 has also been implicated in pre-mRNA splicing, possibly through the timely dephosphorylation of SAP155 and CDC5L mediated by associated PP1 (Beullens, 2002;Tanuma et al, 2008). Furthermore, NIPP1 regulates the protein kinase MELK, a poorly characterized regulator of cell proliferation (Liu et al, 2017;Vulsteke et al, 2004). A multifunctional role of NIPP1 is also indicated by the diverse phenotypes associated with its deletion or overexpression.…”