FOSL1 is a key regulator of a super-enhancer driving TCOF1 expression in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with an unmet clinical need, but its epigenetic regulation remains largely undefined. By performing multiomic profiling, we recently revealed distinct super-enhancer (SE) patterns in different subtypes of breast cancer and identified a number of TNBC-specific SEs that drive oncogene expression. One of these SEs, TCOF₁ SE, was discovered to play an important oncogenic role in TNBC. However, the molecular mechanisms by which TCOF₁ SE promotes the expression of the TCOF₁ gene remain to be elucidated. Here, by using combinatorial approaches of DNA pull-down assay, bioinformatics analysis and functional studies, we identified FOSL¹ as a key transcription factor that binds to TCOF₁ SE and drives its overexpression. shRNA-mediated depletion of FOSL₁ results in significant downregulation of TCOF₁ mRNA and protein levels. Using a dual-luciferase reporter assay and ChIP-qPCR, we showed that binding of FOSL₁ to TCOF₁ SE promotes the transcription of TCOF₁ in TNBC cells. Importantly, our data demonstrated that overexpression of FOSL₁ drives the activation of TCOF₁ SE. Lastly, depletion of FOSL₁ inhibits tumor spheroid growth and stemness properties of TNBC cells. Taken together, these findings uncover the key epigenetic role of FOSL₁ and highlight the potential of targeting the FOSL₁-TCOF₁ axis for TNBC treatment. © The Author(s) 2024