KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway

H Li; X Jiang; Y Yu; W Huang; H Xing; N Y Agar; H W Yang; B Yang; R S Carroll; M D Johnson

doi:10.1038/onc.2014.49

KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway

Oncogene. 2015 Mar 12;34(11):1432-41. doi: 10.1038/onc.2014.49. Epub 2014 Apr 7.

Authors

H Li¹, X Jiang², Y Yu², W Huang², H Xing², N Y Agar², H W Yang², B Yang³, R S Carroll², M D Johnson⁴

Affiliations

¹ 1] Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [2] Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³ Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ 1] Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [2] Program in Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Boston, MA, USA.

PMID: 24704824
DOI: 10.1038/onc.2014.49

Abstract

Aberrant splicing of the cyclin-dependent kinase-associated phosphatase, KAP, promotes glioblastoma invasion in a Cdc2-dependent manner. However, the mechanism by which this occurs is unknown. Here we show that miR-26a, which is often amplified in glioblastoma, promotes invasion in phosphatase and tensin homolog (PTEN)-competent and PTEN-deficient glioblastoma cells by directly downregulating KAP expression. Mechanistically, we find that KAP binds and activates ROCK2. Thus, RNA-mediated downregulation of KAP leads to decreased ROCK2 activity and this, in turn, increases Rac1-mediated invasion. In addition, the decrease in KAP expression activates the cyclin-dependent kinase, Cdk2, and this directly promotes invasion by increasing retinoblastoma phosphorylation, E2F-dependent Cdc2 expression and Cdc2-mediated inactivation of the actomyosin inhibitor, caldesmon. Importantly, glioblastoma cell invasion mediated by this pathway can be antagonized by Cdk2/Cdc2 inhibitors in vitro and in vivo. Thus, two distinct RNA-based mechanisms activate this novel KAP/ROCK2/Cdk2-dependent invasion pathway in glioblastoma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actomyosin / antagonists & inhibitors
Brain Neoplasms / pathology
CDC2 Protein Kinase
Calmodulin-Binding Proteins / antagonists & inhibitors
Cell Line, Tumor
Cyclin-Dependent Kinase 2 / antagonists & inhibitors
Cyclin-Dependent Kinase 2 / genetics
Cyclin-Dependent Kinase 2 / metabolism*
Cyclin-Dependent Kinase Inhibitor Proteins / biosynthesis
Cyclin-Dependent Kinase Inhibitor Proteins / genetics
Cyclin-Dependent Kinase Inhibitor Proteins / metabolism*
Cyclin-Dependent Kinases / antagonists & inhibitors
Cyclin-Dependent Kinases / biosynthesis
Dual-Specificity Phosphatases / biosynthesis
Dual-Specificity Phosphatases / genetics
Dual-Specificity Phosphatases / metabolism*
E2F Transcription Factors / physiology
Enzyme Activation
Glioblastoma / pathology*
Humans
MicroRNAs / antagonists & inhibitors
MicroRNAs / genetics
MicroRNAs / physiology*
Neoplasm Invasiveness
PTEN Phosphohydrolase / metabolism
Phosphorylation
Protein Binding
RNA Interference
RNA, Small Interfering
Retinoblastoma Protein / metabolism
rac1 GTP-Binding Protein / physiology
rho-Associated Kinases / metabolism*

Substances

Calmodulin-Binding Proteins
Cyclin-Dependent Kinase Inhibitor Proteins
E2F Transcription Factors
MIRN26A microRNA, human
MicroRNAs
RAC1 protein, human
RNA, Small Interfering
Retinoblastoma Protein
Actomyosin
ROCK2 protein, human
rho-Associated Kinases
CDC2 Protein Kinase
CDK1 protein, human
CDK2 protein, human
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases
CDKN3 protein, human
Dual-Specificity Phosphatases
PTEN Phosphohydrolase
PTEN protein, human
rac1 GTP-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding