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Isoprenylcysteine carboxylmethyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal.

Authors
  • Chai, Tin Fan1, 2
  • Manu, Kanjoormana Aryan1
  • Casey, Patrick J1, 3
  • Wang, Mei4, 5
  • 1 Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore. , (Singapore)
  • 2 Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore. , (Singapore)
  • 3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA.
  • 4 Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore. [email protected] , (Singapore)
  • 5 Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore. [email protected] , (Singapore)
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Jul 01, 2020
Volume
39
Issue
31
Pages
5373–5389
Identifiers
DOI: 10.1038/s41388-020-1364-7
PMID: 32561852
Source
Medline
Language
English
License
Unknown

Abstract

Cancer stem cells possess the capacity for self-renewal and resistance to chemotherapy. It is therefore crucial to understand the molecular regulators of stemness in the quest to develop effective cancer therapies. TAZ is a transcription activator that promotes stem cell functions in post-development mammalian cells; suppression of TAZ activity reduces or eliminates cancer stemness in select cancers. Isoprenylcysteine carboxylmethyltransferase (ICMT) is the unique enzyme of the last step of posttranslational prenylation processing pathway that modifies several oncogenic proteins, including RAS. We found that suppression of ICMT results in reduced self-renewal/stemness in KRAS-driven pancreatic and breast cancer cells. Silencing of ICMT led to significant reduction of TAZ protein levels and loss of self-renewal ability, which could be reversed by overexpressing mutant KRAS, demonstrating the functional impact of ICMT modification on the ability of KRAS to control TAZ stability and function. Contrary to expectation, YAP protein levels appear to be much less susceptible than TAZ to the regulation by ICMT and KRAS, and YAP is less consequential in regulating stemness characteristics in these cells. Further, we found that the ICMT-dependent KRAS regulation of TAZ was mediated through RAF, but not PI3K, signaling. Functionally, we demonstrate that a signaling cascade from ICMT modification of KRAS to TAZ protein stability supports cancer cell self-renewal abilities in both in vitro and in vivo settings. In addition, studies using the proof-of-concept small molecule inhibitors of ICMT confirmed its role in regulating TAZ and self-renewal, demonstrating the potential utility of targeting ICMT to control aggressive KRAS-driven cancers.

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