Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis.
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.
Chan
Chia-Hsin
CH
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Lee
Szu-Wei
SW
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
Li
Chien-Feng
CF
Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
Wang
Jing
J
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Yang
Wei-Lei
WL
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
Wu
Ching-Yuan
CY
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.|Department of Chinese Medicine; Chang Gung Memorial Hospital-Kaohsiung Medical Center; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University; Kaohsiung, Taiwan.|Graduate Institute of Clinical Medical Sciences, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
Wu
Juan
J
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.|State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
Nakayama
Keiichi I
KI
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan.
Kang
Hong-Yo
HY
Graduate Institute of Clinical Medical Sciences, Chang Gung Memorial Hospital-Koahsiung Medical Center, Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
Huang
Hsuan-Ying
HY
Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center; Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Hung
Mien-Chie
MC
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan.
Pandolfi
Pier Paolo
PP
Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Lin
Hui-Kuan
HK
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
D000818:Animals; D002460:Cell Line; D050881:E1A-Associated p300 Protein; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics; D009362:Neoplasm Metastasis; D009369:Neoplasms; D009687:Nuclear Proteins; D016274:Oncogene Protein p55(v-myc); D011401:Promoter Regions, Genetic; D050828:Protein Inhibitors of Activated STAT; D044786:S-Phase Kinase-Associated Proteins; D044843:SKP Cullin F-Box Protein Ligases; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics*
D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D016274:Oncogene Protein p55(v-myc); D050828:Protein Inhibitors of Activated STAT; D044786:S-Phase Kinase-Associated Proteins; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C485521:Miz1 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D020742:rhoA GTP-Binding Protein
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