Jia Yunlu, Chen Yongxia, Chen Ming, He Mengye, Xu Suzhen, Li Han, Lin Xuanyi, Wang Linbo, Zhou Jichun, Shen Peng, Luo Xiao, Zhang Xiaochen, Ruan Jian
Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310020, China.
Cancer Lett. 2024 Dec 28;611:217423. doi: 10.1016/j.canlet.2024.217423.
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.
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，缺乏有效的靶向治疗方法，预后较差。在本研究中，我们利用表观基因组图谱、TCGA数据库和临床样本，揭示了HJURP在TNBC中的关键作用。我们的研究表明，HJURP表达升高与不良预后、转移进展和乳腺癌晚期密切相关。RNA测序分析表明，HJURP沉默抑制了与TNBC恶性表型相关的转录特征，从而抑制细胞增殖、迁移、侵袭、上皮-间质转化（EMT），并促进细胞凋亡。敲低HJURP会损害MDA-MB231移植瘤的生长，降低shHJURP组中KI67和HJURP的表达。公开可用的数据集显示，与携带野生型p53（wtp53）的TNBC细胞相比，携带突变型p53（mutp53）的TNBC细胞中HJURP表达存在差异，这突出了TNBC侵袭性的潜在机制。从机制上讲，我们发现wtp53的缺失或突变会增强HJURP的表达，而wtp53的积累会抑制HJURP的转录。我们阐明了一个调控轴，其中wtp53正向调节转录因子FOXM1和E2F1，它们与H3K27ac形成复合物，优先与HJURP增强子结合，驱动其转录。靶向增强子区域的CRISPR干扰导致HJURP表达降低和类似于HJURP敲低的表型，同时E2F1、FOXM1和H3K27ac与增强子的结合减少。从转化医学的角度来看，我们发现携带wtp53且HJURP水平高的乳腺癌患者生存率显著降低。总体而言，我们的研究结果确定增强子驱动的HJURP是一种关键的分子旁路，它抑制了wtp53的肿瘤抑制和促凋亡作用。靶向HJURP提出了一种有吸引力的治疗策略，可特异性抑制p53突变型TNBC的肿瘤增殖、转移和侵袭。
