Oncogenic HJURP is driven by P53/ E2F1/FOXM1-axis regulated enhancer and potentiates TNBC proliferation and invasion

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor outcomes and lacks effective targeted therapies. We utilized the epigenomic landscape, TCGA database and clinical samples to show the activation of HJURP in TNBC, which is associated with poor prognosis, metastasis, and advanced stage. RNA-seq analysis of HJURP silencing induced malignant phenotypes-related transcriptional signatures of TNBC. Specifically, knock-down of HJURP suppressed cell proliferation, migration, invasion, EMT progress, and induced apoptosis of TNBC. Analysis of publicly available data sets revealed that HJURP is elevated in mutP53 vs. wtP53 breast cancer cells. Inactivation of wild type P53, by loss or mutation of wtP53, increased HJURP expression, whereas accumulation of wild-type P53 reduced HJURP promoter activity and HJURP transcription. We found the activation of HJURP in TNBC was driven by the mutant P53-regulated enhancer instead of genetic alteration. P53 positively regulated the expression of transcription factor FOXM1 and E2F1, and the FOXM1/E2F1/H3K27ac complex preferentially occupied the HJURP-enhancer and regulated HJURP transcription by binding to the active elements. CRISPR interference of enhancer structure or specific disruption of enhancer complex inhibited HJURP transcription and phenocopied HJURP silencing, leading to impaired E2F1, FOXM1 and H3K27ac binding affinity. Consistent with this result, knock-down of FOXM1 or E2F1 reduced HJURP expression in TNBC cells containing mutant alleles of P53 gene. Lastly, we uncovered marked decreases in survival of breast cancer patients expressing high HJURP levels carrying wtP53. Our findings identify enhancer-driven HJURP as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wtP53. Targeting HJURP allows for effective suppression of tumor invasion and attenuating metastasis in P53-mutant TNBC.