TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.
Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Xiaohua
X
Su
Deepavali
D
Chakravarti
Min Soon
MS
Cho
Lingzhi
L
Liu
Young Jin
YJ
Gi
Yu-Li
YL
Lin
Marco L
ML
Leung
Adel
A
El-Naggar
Chad J
CJ
Creighton
Milind B
MB
Suraokar
Ignacio
I
Wistuba
Elsa R
ER
Flores
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D043244:Ribonuclease III / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D035683:MicroRNAs; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins; D004722:Endoribonucleases; C408087:DICER1 protein, human; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases