PUM1 represses CDKN1B translation and contributes to prostate cancer progression

摘要

Posttranscriptional regulation of cancer gene expression programs plays a vital role in carcinogenesis;identifying the critical regulators of tumorigenesis and their molecular targets may provide novel strategies for cancer diagnosis and therapeutics.Highly conserved RNA-binding protein Pumilio-1(PUM1)regulates mouse growth and cell proliferation,propelling us to examine its role in cancer.We found human PUM1 is highly expressed in a diverse group of cancer,including prostate cancer;enhanced PUM1 expression is also correlated with reduced survival among prostate cancer patients.Detailed expression analysis in twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and protein levels.Knockdown of PUM1 reduced prostate cancer cell proliferation and colony formation,and subcutaneous injection of PUM1 knockdown cells led to reduced tumor size.Downregulation of PUM1 in prostate cancer cells consistently elevated cyclin-dependent kinase inhibitor 1B(CDKN1B)protein expression through increased translation but did not impact its mRNA level,while overexpression of PUM1 reduced CDKN1B protein level.Our finding established a critical role of PUM1 mediated translational control,particularly the PUM1-CDKN1B axis,in prostate cancer cell growth and tumorigenesis.We proposed that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of CDKN1B protein expression in diverse cancers and potential targets for therapeutics development.