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Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis.

ABSTRACT: The RhoA GTPase is crucial in numerous biological functions and is linked to cancer metastasis. However, the understanding of the molecular mechanism responsible for RhoA transcription is still very limited. Here we show that RhoA transcription is orchestrated by the Myc-Skp2-Miz1-p300 transcriptional complex. Skp2 cooperates with Myc to induce RhoA transcription by recruiting Miz1 and p300 to the RhoA promoter independently of Skp1-Cullin-F-box protein containing complex (SCF)-Skp2 E3 ligase activity. Deficiency of this complex results in impairment in RhoA expression, cell migration, invasion, and breast cancer metastasis, recapitulating the phenotypes observed in RhoA knockdown, and RhoA restoration rescues the defect in cell invasion. Overexpression of the Myc-Skp2-Miz1 complex is found in metastatic human cancers and is correlated with RhoA expression. Our study provides insight into how oncogenic Skp2 and Myc coordinate to induce RhoA transcription and establishes a novel SCF-Skp2 E3-ligase-independent function for oncogenic Skp2 in transcription and cancer metastasis.

SUBMITTER: Chan CH

PROVIDER: S-EPMC3855841 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis.

Chan Chia-Hsin CH Lee Szu-Wei SW Li Chien-Feng CF Wang Jing J Yang Wei-Lei WL Wu Ching-Yuan CY Wu Juan J Nakayama Keiichi I KI Kang Hong-Yo HY Huang Hsuan-Ying HY Hung Mien-Chie MC Pandolfi Pier Paolo PP Lin Hui-Kuan HK

Nature cell biology 20100411 5

The RhoA GTPase is crucial in numerous biological functions and is linked to cancer metastasis. However, the understanding of the molecular mechanism responsible for RhoA transcription is still very limited. Here we show that RhoA transcription is orchestrated by the Myc-Skp2-Miz1-p300 transcriptional complex. Skp2 cooperates with Myc to induce RhoA transcription by recruiting Miz1 and p300 to the RhoA promoter independently of Skp1-Cullin-F-box protein containing complex (SCF)-Skp2 E3 ligase ac ...[more]

PMID: 20383141

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Project description:The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors and were of lower morbidity than wild-type cells. In vitro studies used PDX and 1321N1 glioblastoma cells to examine functional responses to sphingosine 1-phosphate (S1P), a GPCR agonist that activates RhoA signaling, demonstrated that YAP signaling was required for cell migration and invasion, whereas MRTF-A was required for cell adhesion; both YAP and MRTF-A were required for proliferation. Gene expression analysis by RNA-sequencing of S1P-treated MRTF-A or YAP knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor (TF)), a target gene regulated selectively through YAP, blocked cell invasion and migration, whereas knockdown of HBEGF (heparin-binding epidermal growth factor-like growth factor), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of target genes regulated through either or both YAP and MRTF-A. Expression of TF and HBEGF was also selectively decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in preclinical GBM models and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM.

Project description:The role of YAP (Yes associated protein 1 gene) and MRTF-A (Megakaryoblastic Leukemia gene, MLK1), two transcriptional co-activators regulated downstream of GPCRs (G-protein coupled receptor) and RhoA, in growth of glioblastoma cells and in vivo GBM tumor development was explored using human glioblastoma cell lines (1321N1) and tumor initiating cells derived from patient derived xenografts (PDX)PDX (GSC-23) cells. Knockdown of these co-activators in PDX cells using shRNA significantly attenuated in vitro proliferation and stemness assessed by limiting dilution and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors with lower morbidity than wild-type cells. In vitro studies of cellular responses to the GPCR agonist sphingosine 1-phosphate (S1P) demonstrated that YAP was required for glioblastoma cell invasion and migration, whereas MRTF-A, was required for cell adhesion. S1P- stimulated proliferation was abolished by knockout of either YAP or MRTF-A. Gene expression analysis by RNA-sequencing of S1P- treated 1321N1 cells in which MRTF-A and or YAP were deleted knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor; TF), a target gene regulated selectively through YAP, when knocked down blocked 1321N1 cell invasion and migration, whereas knockdown of HBEGF (Hheparin binding EGF-like growth factor) (HBEGF), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of several target genes dually regulated through both YAP and MRTF-A (CCN1 and MYC) or of those regulated by either factor. Expression of these same genes was decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in the in vivo GBM tumor environment and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM.

Dataset Information

Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis.

Publications

Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis.

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