Oncogenic HJURP enhancer promotes the aggressive behavior of triple-negative breast cancer in association with p53/E2F1/FOXM1-axis.

Abstract

Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, lacking effective targeted therapies and presenting with a poor prognosis. In this study, we utilized the epigenomic landscape, TCGA database, and clinical samples to uncover the pivotal role of HJURP in TNBC. Our investigation revealed a strong correlation between elevated HJURP expression and unfavorable prognosis, metastatic progression, and late-stage of breast cancer. RNA-seq analysis indicated that HJURP silencing suppressed transcriptional signatures associated with malignant phenotypes of TNBC, thereby inhibiting cell proliferation, migration, invasion, epithelial-to-mesenchymal transition (EMT), and promoting apoptosis. Knockdown of HJURP impaired the growth of MDA-MB231-engrafted tumors, reducing KI67 and HJURP expression in the shHJURP group. Publicly available datasets showed differential expression of HJURP in TNBC cells harboring mutant p53 (mutp53) compared to those with wild-type p53 (wtp53), highlighting a potential mechanism underlying TNBC's aggressiveness. Mechanistically, we established that loss or mutation of wtp53 enhances HJURP expression, whereas wtp53 accumulation restrains HJURP transcription. We elucidated a regulatory axis where wtp53 positively modulates the transcription factors FOXM1 and E2F1, which form a complex with H3K27ac to bind preferentially to the HJURP enhancer, driving its transcription. CRISPR interference targeting the enhancer region resulted in diminished HJURP expression and phenotypes reminiscent of HJURP knockdown, accompanied by reduced binding of E2F1, FOXM1, and H3K27ac to the enhancer. In a translational perspective, we found marked decreases in survival of breast cancer patients expressing high HJURP levels carrying wtp53. Collectively, our findings identify enhancer-driven HJURP as a pivotal molecular bypass that suppresses the tumor-suppressive and pro-apoptotic effects of wtp53. Targeting HJURP presents a compelling therapeutic strategy to inhibit tumor proliferation, metastasis, and invasiveness specifically p53-mutant TNBC.