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Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms.

ABSTRACT: Despite extensive effort, there has been limited progress in the development of direct RAS inhibitors. Targeting isoprenylcysteine carboxylmethyltransferase (ICMT), a unique enzyme of RAS post-translational modification, represents a promising strategy to inhibit RAS function. However, there lacks direct genetic evidence on the role of ICMT in RAS-driven human cancer initiation and maintenance. Using CRISPR/Cas9 genome editing, we have created Icmt loss-of-function isogenic cell lines for both RAS-transformed human mammary epithelial cells (HME1) and human cancer cell lines MiaPaca-2 and MDA-MB-231 containing naturally occurring mutant KRAS. In both in vitro and in vivo tumorigenesis studies, Icmt loss-of-function abolishes the tumor initiation ability of all major isoforms of mutant RAS in HME1 cells, and the tumor maintenance capacity of MiaPaca-2 and MDA-MB-231 cells, establishing the critical role of ICMT in RAS-driven cancers.

SUBMITTER: Lau HY

PROVIDER: S-EPMC5502315 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms.

Lau H Y HY Tang J J Casey P J PJ Wang M M

Oncogene 20170213 27

Despite extensive effort, there has been limited progress in the development of direct RAS inhibitors. Targeting isoprenylcysteine carboxylmethyltransferase (ICMT), a unique enzyme of RAS post-translational modification, represents a promising strategy to inhibit RAS function. However, there lacks direct genetic evidence on the role of ICMT in RAS-driven human cancer initiation and maintenance. Using CRISPR/Cas9 genome editing, we have created Icmt loss-of-function isogenic cell lines for both R ...[more]

PMID: 28192404

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