LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis

Xiaodan Ji; Huasong Lu; Qiang Zhou; Kunxin Luo

doi:10.7554/eLife.02907

LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis

Elife. 2014 Jul 22:3:e02907. doi: 10.7554/eLife.02907.

Authors

Xiaodan Ji¹, Huasong Lu², Qiang Zhou¹, Kunxin Luo³

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
² Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States kluo@berkeley.edu.

Abstract

Transcriptional elongation by RNA polymerase (Pol) II is essential for gene expression during cell growth and differentiation. The positive transcription elongation factor b (P-TEFb) stimulates transcriptional elongation by phosphorylating Pol II and antagonizing negative elongation factors. A reservoir of P-TEFb is sequestered in the inactive 7SK snRNP where 7SK snRNA and the La-related protein LARP7 are required for the integrity of this complex. Here, we show that P-TEFb activity is important for the epithelial-mesenchymal transition (EMT) and breast cancer progression. Decreased levels of LARP7 and 7SK snRNA redistribute P-TEFb to the transcriptionally active super elongation complex, resulting in P-TEFb activation and increased transcription of EMT transcription factors, including Slug, FOXC2, ZEB2, and Twist1, to promote breast cancer EMT, invasion, and metastasis. Our data provide the first demonstration that the transcription elongation machinery plays a key role in promoting breast cancer progression by directly controlling the expression of upstream EMT regulators.

Keywords: 7SK snRNA; EMT; LARP7; P-TEFb; breast cancer; super elongation complex.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Transformation, Neoplastic
Disease Progression
Epithelial-Mesenchymal Transition
Female
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Neoplastic*
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Lymphatic Metastasis
Middle Aged
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Positive Transcriptional Elongation Factor B / genetics*
Positive Transcriptional Elongation Factor B / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
RNA, Small Nuclear / genetics*
RNA, Small Nuclear / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Ribonucleoproteins / antagonists & inhibitors
Ribonucleoproteins / genetics*
Ribonucleoproteins / metabolism
Signal Transduction
Snail Family Transcription Factors
Transcription Factors / genetics
Transcription Factors / metabolism
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism
Zinc Finger E-box Binding Homeobox 2

Substances

Forkhead Transcription Factors
Homeodomain Proteins
Larp7 protein, human
Nuclear Proteins
RNA, Small Interfering
RNA, Small Nuclear
Repressor Proteins
Ribonucleoproteins
SNAI1 protein, human
Snail Family Transcription Factors
TWIST1 protein, human
Transcription Factors
Twist-Related Protein 1
ZEB2 protein, human
Zinc Finger E-box Binding Homeobox 2
mesenchyme fork head 1 protein
Positive Transcriptional Elongation Factor B

Abstract

Publication types

MeSH terms

Substances

Grants and funding