Super-enhancer-hijacking RBBP7 potentiates metastasis and stemness of breast cancer via recruiting NuRD complex subunit LSD1.

Background: Aberrant epigenetic and transcriptional events that drive cancer progression could be precisely targeted. We aimed to uncover the epigenetic roles of RBBP7 on breast cancer (BCa) stemness and metastasis.

Methods: The bioinformatic analysis was used to assess the clinical significance of RBBP7 in BCa. CCK8, colony formation, and Transwell assays were utilized to estimate the oncogenic functions of RBBP7. The ChIP-qPCR and dual-luciferase reporter assays were used to investigate the epigenetic mechanisms of RBBP7. Tumor sphere formation assays were conducted to assess the self-renewal abilities of BCa cells. Tail vein injection models were constructed to assess the in vivo metastatic efficiency of BCa cells. The PDOs and PDX models were used to assess the clinical significance of ORY-1001 in suppressing BCa.

Results: Here, we found that RBBP7 is upregulated in BCa and associated with poor prognosis. Functional experiments demonstrated that RBBP7 enhanced BCa proliferation and distal metastasis. Mechanistically, a novel RBBP7-super-enhancer (SE) was identified using multiple databases in BCa. RBBP7-SE sustained high levels of RBBP7 and CRISPR/Cas9-mediated deletion of SE decreased RBBP7 levels and suppressed BCa malignant features. Further, our data showed that RBBP7 may correlate with stemness pathway and significantly potentiated BCa cancer stem-like properties. Additionally, RBBP7 interacts with LSD1 and relies on LSD1 to erase suppressive H3K9me3 markers in promoters of downstream stemness targets (SOX9/SOX2/OCT4/CCND1). Thus, RBBP7 recruits LSD1 to transcriptionally upregulate the expressions of key stemness genes, and promote tumor stemness capacity. Pharmacological inhibition of LSD1 by ORY-1001 effectively repressed RBBP7-high BCa tumor growth, stemness properties, and distant metastasis.

Conclusions: Together, our results establish that the SE-RBBP7-LSD1 axis represents a potential therapeutic target for BCa treatment.