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

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.

Basal‐like mammary carcinomas stimulate cancer stem cell properties through AXL‐signaling to induce chemotherapy resistance

“…Immunofluorescence staining was performed as previously published 25 . For detailed protocol, refer to Data S1.…”

“…Immunofluorescence staining was performed as previously published. 25 For detailed protocol, refer to Data S1. Radar-plot in Figure 3D was designed using Origin 2022 (v. 9.9.0.220).…”

Histone Mono-Ubiquitination in Transcriptional Regulation and Its Mark on Life: Emerging Roles in Tissue Development and Disease

“…Specifically, epithelial-specific deletion of Rnf40 , either heterozygous or homozygous, in a mammary carcinoma mouse model increased their tumor-free survival and decreased the number of tumors they developed along with the kinetics of tumor growth. Complete deletion of Rnf40 showed better results than partial deletion in this case, and no marked morphological changes were observed [ 198 ]. Taken together, these studies indicate that the effect of RNF20/40 on tumorigenesis potential is context-dependent.…”

Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way

“…While in luminal BC cells, silencing of RNF20 inhibited the expression of ER-targeted genes, such as PGR , CXCL12 , and FOXA1 , which promote proliferation and migration ( Tarcic et al, 2017 ). In HER2-positve BC, RNF40 and H2Bub1 promote breast tumorigenesis by transcriptionally activating genes associated with enhanced actin-cytoskeleton dynamics ( Wegwitz et al, 2020 ). The deubiquitinases of H2Bub1, USP22, USP51, USP27X, and USP44 promote BC proliferation, invasion, and tumor growth ( Atanassov et al, 2016 ; Lan et al, 2016 ).…”