title: CHIP buffers heterogeneous Bcl-2 expression levels to prevent augmentation of anticancer drug-resistant cell population.
abstract: 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.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsuchiya
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakajima
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Waku
authors.affiliation: 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.
authors.forename: H
authors.initials: H
authors.lastname: Hiyoshi
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Morishita
authors.affiliation: Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Furumai
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: 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.
authors.forename: H
authors.initials: H
authors.lastname: Kishimoto
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kimura
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Yanagisawa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology*; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin