Tsuchiya M, Nakajima Y, Waku T, Hiyoshi H, Morishita T, Furumai R, Hayashi Y, Kishimoto H, Kimura K, Yanagisawa J
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
Oncogene. 2015 Aug 27;34(35):4656-63. doi: 10.1038/onc.2014.387. Epub 2014 Dec 1.
Many types of cancer display heterogeneity in various features, including gene expression and malignant potential. This heterogeneity is associated with drug resistance and cancer progression. Recent studies have shown that the expression of a major protein quality control ubiquitin ligase, carboxyl terminus of Hsc70-interacting protein (CHIP), is negatively correlated with breast cancer clinicopathological stages and poor overall survival. Here we show that CHIP acts as a capacitor of heterogeneous Bcl-2 expression levels and prevents an increase in the anticancer drug-resistant population in breast cancer cells. CHIP knockdown in breast cancer cells increased variation in Bcl-2 expression levels, an antiapoptotic protein, among the cells. Our results also showed that CHIP knockdown increased the proportion of anticancer drug-resistant cells. These findings suggest that CHIP buffers variation in gene expression levels, affecting resistance to anticancer drugs. In single-cell clones derived from breast cancer cell lines, CHIP knockdown did not alter the variation in Bcl-2 expression levels and the proportion of anticancer drug-resistant cells. In contrast, when clonal cells were treated with a mutagen, the variation in Bcl-2 expression levels and proportion of anticancer drug-resistant cells were altered by CHIP knockdown. These results suggest that CHIP masks genetic variations to suppress heterogeneous Bcl-2 expression levels and prevents augmentation of the anticancer drug-resistant population of breast cancer cells. Because genetic variation is a major driver of heterogeneity, our results suggest that the degree of heterogeneity in expression levels is decided by a balance between genetic variation and the buffering capacity of CHIP.
许多类型的癌症在包括基因表达和恶性潜能在内的各种特征中表现出异质性。这种异质性与耐药性和癌症进展相关。最近的研究表明，一种主要的蛋白质质量控制泛素连接酶，即Hsc70相互作用蛋白的羧基末端（CHIP）的表达与乳腺癌临床病理分期及总体生存率低呈负相关。在此我们表明，CHIP作为异质性Bcl-2表达水平的一种缓冲因子，并防止乳腺癌细胞中抗癌药物耐药群体的增加。乳腺癌细胞中CHIP的敲低增加了细胞间抗凋亡蛋白Bcl-2表达水平的差异。我们的结果还表明，CHIP敲低增加了抗癌药物耐药细胞的比例。这些发现表明，CHIP缓冲基因表达水平的差异，影响对抗癌药物的耐药性。在源自乳腺癌细胞系的单细胞克隆中，CHIP敲低并未改变Bcl-2表达水平的差异及抗癌药物耐药细胞的比例。相反,当克隆细胞用诱变剂处理时，CHIP敲低改变了Bcl-2表达水平的差异及抗癌药物耐药细胞的比例。这些结果表明，CHIP掩盖遗传变异以抑制异质性Bcl-2表达水平，并防止乳腺癌细胞抗癌药物耐药群体的增加。由于遗传变异是异质性的主要驱动因素，我们的结果表明，表达水平的异质性程度由遗传变异与CHIP的缓冲能力之间的平衡决定。
