Kinome inhibition reveals a role for polo‐like kinase 1 in targeting post‐transcriptional control in cancer. Issue 8 (1st February 2021)

• Record Type: Journal Article
• Authors: Al‐Qahtani, Qamraa H.; Moghrabi, Walid N.; Al‐Yahya, Suhad; Al‐Haj, Latifa; Al‐Saif, Maher; Mahmoud, Linah; Al‐Mohanna, Falah; Al‐Souhibani, Norah; Alaiya, Ayodele; Hitti, Edward; Khabar, Khalid S. A.
• Is Part Of: Molecular oncology. Volume 15:Issue 8(2021)
• Page Start: 2120
• Page End: 2139
• Publication Date: 2021-02-01
• Subjects: AU‐rich elements -- kinase inhibitors -- mRNA decay -- post‐transcriptional control -- targeted therapy -- breast cancer; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12897
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Dysfunctions in post‐transcriptional control are observed in cancer and chronic inflammatory diseases. Here, we employed a kinome inhibitor library ( n = 378) in a reporter system selective for 3′‐untranslated region–AU‐rich elements (ARE). Fifteen inhibitors reduced the ARE‐reporter activity; among the targets is the polo‐like kinase 1 (PLK1). RNA‐seq experiments demonstrated that the PLK1 inhibitor, volasertib, reduces the expression of cytokine and cell growth ARE mRNAs. PLK1 inhibition caused accelerated mRNA decay in cancer cells and was associated with reduced phosphorylation and stability of the mRNA decay‐promoting protein, tristetraprolin (ZFP36/TTP). Ectopic expression of PLK1 increased abundance and stability of high molecular weight of ZFP36/TTP likely of the phosphorylated form. PLK1 effect was associated with the MAPK‐MK2 pathway, a major regulator of ARE‐mRNA stability, as evident from MK2 inhibition, in vitro phosphorylation, and knockout experiments. Mutational analysis demonstrates that TTP serine 186 is a target for PLK1 effect. Treatment of mice with the PLK1 inhibitor reduced both ZFP36/TTP phosphorylation in xenograft tumor tissues, and the tumor size. In cancer patients' tissues, PLK1/ARE‐regulated gene cluster was overexpressed in solid tumors and associated with poor survival. The data showed that PLK1‐mediated post‐transcriptional aberration could be a therapeutic target. Abstract : A kinome inhibitor screen identified several kinases operating in post‐transcriptional control. Among those is polo‐like kinase 1 (PLK1), which is overexpressed in cancer, leading to MAPK‐activated protein kinases 2 (MK2)‐dependent phosphorylation and inactivation of the mRNA decay‐promoting protein, tristetraprolin. These events cause overexpression of many cancer genes; thus, therapeutic targeting of PLK1 kinase may restore post‐transcriptional defects in disease.