The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis

Florian Wegwitz,Anastasija Pejkovska,Klaus Pantel,Markus Glatzel,Robyn Laura Kosinsky,Harriet Wikman,Evangelos Prokakis,Steven A Johnsen

doi:10.1038/s41419-020-03081-w

Abstract

The HER2-positive breast cancer subtype (HER2+-BC) displays a particularly aggressive behavior. Anti-HER2 therapies have significantly improved the survival of patients with HER2+-BC. However, a large number of patients become refractory to current targeted therapies, necessitating the development of new treatment strategies. Epigenetic regulators are commonly misregulated in cancer and represent attractive molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by the heterodimeric ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2+-BC. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin-cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2+-BC, revealing the H2B monoubiquitination axis as a possible tumor context-dependent therapeutic target in breast cancer.

Highlights

Breast cancer (BC) is the most common form of cancer in the female population[1]
We examined the relationship between RNF40 mRNA levels and survival in HER2+-BC patients using publically available data (TCGA, KM plotter) and observed that high levels of RNF40 expression were associated with reduced overall, relapse-free and distant metastasis-free survival (Fig. 1D, E and Fig. S1C)
These data demonstrate that RNF40 expression is not lost in metastatic HER2+-BC and that its expression correlates with poor prognosis in these patients

Summary

Introduction

Breast cancer (BC) is the most common form of cancer in the female population[1]. The survival rates of BC vary greatly and strongly depend on both early detection as well as the molecular subtype[2]. The HER2-positive breast cancer subtype (HER2+-BC) is invasive and displays a poorer prognosis compared to hormone receptorpositive (ER+ or/and PR+) BC3. While current anti-HER2 therapies are initially highly effective for many BC patients with HER2+-tumors, a significant number of patient tumors develop therapy resistance, tumor relapse, and disease progression[4]. Precision oncology approaches aim to utilize or develop novel targeted therapies that exploit tumor-specific dependencies and/or vulnerabilities based on specific molecular alterations present in a given tumor or molecular subtype[5]. Due to the reversible nature of many of these changes, numerous substances targeting epigenetic factors are currently in various stages of preclinical and clinical testing to determine their efficacy as anticancer therapies[6]

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Results

Conclusion