Open AccessInhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway
Author(s) -
Chen Song,
Zhou Qiang,
Guo Zicheng,
Wang Yejinpeng,
Wang Lu,
Liu Xuefeng,
Lu Mengxin,
Ju Lingao,
Xiao Yu,
Wang Xinghuan
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14878
Subject(s) - cell cycle , cancer research , cell cycle checkpoint , cell growth , biology , gene silencing , dna damage , retinoblastoma protein , cyclin d1 , e2f , cell , microbiology and biotechnology , dna , gene , biochemistry , genetics
We aimed to investigate the biological function of MELK and the therapeutic potential of OTSSP167 in human bladder cancer (BCa). First, we observed overexpression of MELK in BCa cell lines and tissues and found that it was associated with higher tumour stage and tumour grade, which was consistent with transcriptome analysis. High expression of MELK was significantly correlated with poor prognosis in BCa patients, and MELK was found to have a role in the cell cycle, the G1/S transition in mitosis, and DNA repair and replication. Furthermore, BCa cells presented significantly decreased proliferation capacity following silencing of MELK or treatment with OTSSP167 in vitro and in vivo. Functionally, reduction in MELK or treatment of cells with OTSSP167 could induce cell cycle arrest and could suppress migration. In addition, these treatments could activate phosphorylation of ATM and CHK2, which would be accompanied by down‐regulated MDMX, cyclin D1, CDK2 and E2F1; however, p53 and p21 would be activated. Opposite results were observed when MELK expression was induced. Overall, MELK was found to be a novel oncogene in BCa that induces cell cycle arrest via the ATM/CHK2/p53 pathway. OTSSP167 displays potent anti‐tumour activities, which may provide a new molecule‐based strategy for BCa treatment.