# Relaxed Polymerase Pausing as a Driver of Epigenetic Plasticity and Cancer Cell Invasion

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $428,899

## Abstract

Project Summary
The development of distant metastases accounts for a significant proportion of breast cancer mortality; as many
as 30% of patients initially diagnosed at an early stage will eventually progress to metastatic disease. A key early
step in metastatic progression is an increase in cellular plasticity that enables a subset of tumor cells to lose
residual epithelial features and gain migratory and invasive behavior, molecularly reflected in the epithelial to
mesenchymal transition (EMT). Considerable evidence now points to cancer-associated EMT as a highly
dynamic and reversible process with disseminated cancer cells exhibiting many hybrid intermediate states
(partial-EMT) proposed to possess the greatest potential for aggressive, stem-like, behavior. However, the
epigenetic mechanisms that control such phenotypic plasticity and the role of this process in early invasion
remain incompletely understood. Recently we discovered that the local regulation of RNA polymerase (Pol II)
pause release by the histone methyltransferase SUV420H2 plays an important role in stabilizing the epithelial
‘identity’ of luminal breast cancer cells and in so doing, suppresses breast cancer cell invasion. Specifically, we
find that the local conversion of H4K20me1 to me3 by SUV420H2 enforces RNA polymerase pausing by blocking
recruitment of the MOF/MSL complex, which is in turn necessary for the acetylation of H4K16, recruitment of
pTEFb and Pol II pause release. We further find that SUV420H2-mediated repression constrains the
mesenchymal program in luminal breast epithelial cells, yet is directed to new sites upon TGF-β induced EMT.
SUV420H2 is downregulated in triple negative/basal subtype of breast cancers, and its forced downregulation
or inhibition promotes collective invasion in breast cell spheroids grown in 3D. These and other findings lead us
to propose that the relaxation of SUV420H2-mediated Pol II pausing control is one source of the epigenetic
plasticity and transcriptional heterogeneity that underlies breast cancer cell adaptation and the emergence of
tumor cells with invasive properties. Using a combination of precision run-on sequencing (Pro-seq) and native
chromatin analyses via CUT&Tag technology, we will determine the how the SUV420H2 mediated pause
constraints enforces phenotypic stability and how loss of these constraints allows for transcriptional promiscuity.
We will explore the role of the HEXIM1 / 7SK snRNP complex as a novel ‘reader’ of histone H4 modifications
and its role in SUV420H2-mediated pause control. Lastly, we will determine the impact of dysregulated Pol II
pausing dynamics on transcriptional diversity and the emergence of breast cells with invasive “leader” potential
in a 3D spheroid model of collective invasion. Over the long term, the results of our studies will provide important
insight into the mechanisms underlying epigenetic plasticity and its role in tumor cell adaptation, and a framework
for the development of nove...

## Key facts

- **NIH application ID:** 10235908
- **Project number:** 1R01CA250531-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Paula M. Vertino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $428,899
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235908

## Citation

> US National Institutes of Health, RePORTER application 10235908, Relaxed Polymerase Pausing as a Driver of Epigenetic Plasticity and Cancer Cell Invasion (1R01CA250531-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10235908. Licensed CC0.

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