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.
