Isoprenylcysteine carboxylmethyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal
Open accessAbstract
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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Alternative compounds targeting ICMT and RCE1 have been tested and show anti-cancer activity in cell and animal models.
“Alternative compounds targeting enzymes that modify RAS proteins post-prenylation, ICMT and RCE1, have been tested and show anti-cancer activity in cell and animal models [41,42].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [42]
The Results section on ICMT inhibitors (page unavailable) reports that two ICMT-targeting compounds reduced tumor-sphere formation in cancer-cell cultures. The mouse experiments used genetic ICMT knockdown with chemotherapy, not those compounds. The retrieved passages do not report tests of RCE1-targeting compounds, so this source does not support the full claim. (LLM, conf=0.87)
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Catalytic properties of the integral membrane RAS protease Rce1
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- Authors
- Chai, T. F., Manu, K. A., Casey, P. J., & Wang, M.
- Affiliations
- National University of Singapore (SG)
- Duke-NUS Medical School (SG)
- Duke Medical Center (US)
- Corresponding author
- Wang, Mei
- Venue
- Oncogene
- Published
- 2020-06-19
- Volume
- 39
- Issue
- 31
- Pages
- 5373-5389
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC7391290
- OpenAlex
- W3036305165
- Cited by
- 20
- References
- 82
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2022: 7 · 2021: 3
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Oncogene (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, India
- Medical Research Council
- National Medical Research Council (CIRG/1486/2018, 1486/2018, NMRC/CIRG/1486/2018)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- KRAS, TAZ, YAP, cancer stem cells, protein prenylation, protein stability, Raf signaling, pancreatic cancer, breast cancer, stemness
- MeSH terms
- Cell Self Renewal, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Gemcitabine, Animals, Breast Neoplasms, Deoxycytidine, Doxorubicin, Female, Humans, Mutation, Pancreatic Neoplasms, Protein Methyltransferases, Neoplastic Stem Cells, Trans-Activators, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, MAP Kinase Signaling System, Cell Line, Tumor, Mice, HEK293 Cells, Heterografts
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