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

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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.

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Xiaodan Ji

Univeristy of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Huasong Lu

University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Qiang Zhou

University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Kunxin Luo

University of California, Berkeley, Berkeley, United States

For correspondence
kluo@berkeley.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animals were handled according to the approved animal protocol (#R239) by the Institutional Animal Care and Use Committee (ACUC) of the University of California, Berkeley. All animal experiments were performed following the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.