Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program.
Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program.
复制标题
DOI：
10.1158/0008-5472.can-16-2140
复制
发表时间：
2018-05-15
期刊：
影响因子：
11.2
通讯作者：
Band H
中科院分区：
文献类型：
--
作者：
Luan H;Mohapatra B;Bielecki TA;Mushtaq I;Mirza S;Jennings TA;Clubb RJ;An W;Ahmed D;El-Ansari R;Storck MD;Mishra NK;Guda C;Sheinin YM;Meza JL;Raja S;Rakha EA;Band V;Band H
CHIP/STUB1泛素连接酶是HSP90/HSC70的负性共伴侣，其表达在包括乳腺癌在内的几种癌症中减少或缺失。通过广泛和充分注释的乳腺癌组织收集，我们确定了细胞核CHIP的缺失，而不是细胞质CHIP的缺失，以预测更侵袭性的肿瘤发生和更短的患者生存期，三分之二的ErbB2+和三阴性乳腺癌以及三分之一的ER+乳腺癌中CHIP的缺失。CHIP在乳腺癌患者来源的异种移植肿瘤、ErbB2+和三阴性乳腺癌细胞系中表达降低。ErbB2+细胞系中异位CHIP表达抑制体外致癌特性和体内异种移植物肿瘤生长。对CHIP调节的核转录因子进行无偏筛选，发现许多dna结合活性被CHIP上调或下调的候选因子。我们将髓系锌指1 （Myeloid Zinc Finger 1, MZF1）作为CHIP靶点，因为它最近被发现是ErbB2下游组织蛋白酶B/L （CTSB/L）介导的肿瘤细胞侵袭的正调节因子。我们发现CHIP在ErbB2+和其他乳腺癌细胞系中负调控CTSB/L的表达。CTSB抑制可消除体外侵袭和基质降解，阻止ErbB2+乳腺癌细胞系异种移植物生长。我们得出的结论是，CHIP的缺失重塑了细胞转录组，释放了关键的促癌途径，如组织蛋白酶家族的基质降解酶，其成分可以为乳腺癌和其他CHIP表达缺失的癌症提供新的治疗机会。
CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two-thirds of ErbB2+ and triple-negative breast cancers and in one-third of ER+ breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2+ and triple-negative breast cancer cell lines. Ectopic CHIP expression in ErbB2+ lines suppressed in vitro oncogenic traits and in vivo xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up- or down-regulated by CHIP. We characterized Myeloid Zinc Finger 1 (MZF1) as a CHIP target given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2+ and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation in vitro and halts ErbB2+ breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression.