Abstract
The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1-3 co-activators to promote downstream transcription. Furthermore, we show that Tead-AP1 cooperation regulates the activity of the Dock-Rac/CDC42 module and drives the expression of a unique core set of target genes, thereby directing cell migration and invasion. Together, our data unveil a critical regulatory mechanism underlying Tead- and AP1-controlled transcriptional and functional outputs in cancer cells.
Keywords
AP1
Tead
invasion
transcriptional regulation
MeSH 主题词
Base Sequence
Cell Line, Tumor
Cell Movement
Cluster Analysis
DNA-Binding Proteins/metabolism
Genome, Human
Humans
JNK Mitogen-Activated Protein Kinases/metabolism
Models, Biological
Molecular Sequence Data
Muscle Proteins/metabolism
Neoplasm Invasiveness
Neoplasms/genetics,pathology
Protein Binding
Regulatory Sequences, Nucleic Acid/genetics
TEA Domain Transcription Factors
Transcription Factor AP-1/metabolism
Transcription Factors/metabolism
Transcription, Genetic
化学物质
DNA-Binding Proteins
Muscle Proteins
TEA Domain Transcription Factors
TEAD4 protein, human
Transcription Factor AP-1
Transcription Factors
JNK Mitogen-Activated Protein Kinases
作者与单位
共 12 位作者，点击展开单位 / ORCID
Liu Xiangfan
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Li Huapeng
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Rajurkar Mihir
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Li Qi
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cotton Jennifer L
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Ou Jianhong
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Zhu Lihua J
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Goel Hira L
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Mercurio Arthur M
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Park Joo-Seop
Divisions of Pediatric Urology and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Davis Roger J
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA.
Mao Junhao
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address:
[email protected].
