The histone 2B E3 ligase RNF40 controls the metabolic state in triple-negative breast cancer

Among all breast cancer (BC) subtypes, triple-negative breast cancer (TNBC) is the most difficult entity to treat due to the lack of targeted therapies. Cancer stem cells (CSCs) are strongly enriched in TNBCs and are responsible for the rapid development of chemotherapy resistance and metastasis. Interestingly, an increasing body of evidence demonstrates deep implications of the epigenetic mark histone 2B monoubiquitination (H2Bub1) and its obligatory E3 ligase complex, RNF20/RNF40, in the biology of numerous human cancers, including BC. We recently uncovered that H2Bub1 and RNF40 play a critical tumor-supportive role in HER2-positive BC as well as in colorectal carcinoma. However, to date, the role and clinical value of RNF40 in TNBC have not been addressed. In the present study, we demonstrate that RNF40 supports the mammary gland stem-cell properties in vivo. As TNBC aggressiveness strongly relies on CSC properties, we asked if RNF40 could control the aggressiveness of TNBC. Utilizing publicly available clinical datasets and a BC tissue microarray, we confirmed that high RNF40 expression is associated with a poor survival outcome in TNBC patients. To explore the underlying mechanism, we performed a combination of high throughput sequencing approaches (RNA- and ChIP-sequencing) upon RNF40 knockdown in TNBC cell lines. Thereby, we demonstrated that RNF40-driven H2Bub1 controls the Hippo-YAP1 signaling activity over the glycolysis/AMPK-axis. Collectively, our study unveils a novel tumor-supportive role of RNF40 and reinforces the potential of the H2Bub1-pathway as a possible therapeutic target to combat the CSC-driven aggressive behavior of TNBC.

Publication History

Article published online:
21 June 2022