Abstract
BackgroundDeregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that decreasing MYC expression may have significant therapeutic value. CIP2A is an oncogenic factor that regulates MYC expression. CIP2A is overexpressed in colorectal cancer (CRC), and its expression levels are an independent marker for long-term outcome of CRC. Previous studies suggested that CIP2A controls MYC protein expression on a post-transcriptional level.MethodsTo determine the mechanism by which CIP2A regulates MYC in CRC, we dissected MYC translation and stability dependent on CIP2A in CRC cell lines.ResultsKnockdown of CIP2A reduced MYC protein levels without influencing MYC stability in CRC cell lines. Interfering with proteasomal degradation of MYC by usage of FBXW7-deficient cells or treatment with the proteasome inhibitor MG132 did not rescue the effect of CIP2A depletion on MYC protein levels. Whereas CIP2A knockdown had marginal influence on global protein synthesis, we could demonstrate that, by using different reporter constructs and cells expressing MYC mRNA with or without flanking UTR, CIP2A regulates MYC translation. This interaction is mainly conducted by the MYC 5′UTR.ConclusionsThus, instead of targeting MYC protein stability as reported for other tissue types before, CIP2A specifically regulates MYC mRNA translation in CRC but has only slight effects on global mRNA translation. In conclusion, we propose as novel mechanism that CIP2A regulates MYC on a translational level rather than affecting MYC protein stability in CRC.
Highlights
With more than 1.2 million newly diagnosed cases per year, colorectal cancer (CRC) is the most common gastrointestinal malignancy [1]
It has been clearly demonstrated that cancerous inhibitor of protein phosphatase 2A (CIP2A) reduces MYC expression post-transcriptionally
Mouse embryonic fibroblasts (MEF) isolated from CIP2A-deficient (CIP2AHOZ) mice show the same amount of MYC mRNA as wild-type mice, but harbor lower MYC protein levels after serum stimulation [20]
Summary
With more than 1.2 million newly diagnosed cases per year, colorectal cancer (CRC) is the most common gastrointestinal malignancy [1]. MYC mRNA translation and stability are enhanced in cancer [4]. One major post-transcriptional regulator of MYC protein is the cancerous inhibitor of protein phosphatase 2A (CIP2A), which was identified as a human oncoprotein [5]. CIP2A is overexpressed in human tumor entities including CRC, gastric cancer, head and neck squamous cell carcinoma, breast cancer, prostate cancer, and lymphoma [6,7,8]. CIP2A is an oncogenic factor that regulates MYC expression. CIP2A is overexpressed in colorectal cancer (CRC), and its expression levels are an independent marker for long-term outcome of CRC. Previous studies suggested that CIP2A controls MYC protein expression on a post-transcriptional level
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
