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P53-independent p21 induction by MELK inhibition.

ABSTRACT: MELK play critical roles in human carcinogenesis through activation of cell proliferation, inhibition of apoptosis and maintenance of stemness. Therefore, MELK is a promising therapeutic target for a wide range of cancers. Although p21 is a well-known p53-downstream gene, we found that treatment with a potent MELK inhibitor, OTS167, could induce p21 protein expression in cancer cell lines harboring loss-of-function TP53 mutations. We also confirmed that MELK knockdown by siRNA induced the p21 expression in p53-deficient cancer cell lines and caused the cell cycle arrest at G1 phase. Further analysis indicated that FOXO1 and FOXO3, two known transcriptional regulators of p21, were phosphorylated by MELK and thus be involved in the induction of p21 after MELK inhibition. Collectively, our herein findings suggest that MELK inhibition may be effective for human cancers even if TP53 is mutated.

SUBMITTER: Matsuda T

PROVIDER: S-EPMC5601624 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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p53-independent p21 induction by MELK inhibition.

Matsuda Tatsuo T Kato Taigo T Kiyotani Kazuma K Tarhan Yunus Emre YE Saloura Vassiliki V Chung Suyoun S Ueda Koji K Nakamura Yusuke Y Park Jae-Hyun JH

Oncotarget 20170615 35

MELK play critical roles in human carcinogenesis through activation of cell proliferation, inhibition of apoptosis and maintenance of stemness. Therefore, MELK is a promising therapeutic target for a wide range of cancers. Although p21 is a well-known p53-downstream gene, we found that treatment with a potent MELK inhibitor, OTS167, could induce p21 protein expression in cancer cell lines harboring loss-of-function <i>TP53</i> mutations. We also confirmed that MELK knockdown by siRNA induced the ...[more]

PMID: 28938528

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Chronic p53-independent p21 expression deregulates replication licensing, leading to genomic instability

Project description:P53 independent P21 expression deregulates replication licensing , leading to genomic instability

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Author Correction: Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability.

Project description: Not available

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