Centromere Gene Misregulation Is A Major Source Of Chromosomal Instability In Human Cancers And Predicts Patient Response To Specific Therapies

Chromosomal instability (CIN) is a cancer hallmark that contributes to tumor heterogeneity and other malignant properties. Aberrant centromere function causes CIN through chromosome missegregation in experimental systems. CENP-A is a histone H3 variant found at centromeres. Centromere is regulated epigenetically by replenishing CENP-A chromatin during cell divisions. This process requires a dedicated CENP-A chaperone called HJURP and other factors. However, we are lack of a comprehensive understanding about whether these proteins are involved in clinical cancers, and how centromere misregulation may contribute to cancer development. Here, basing on our previous findings in Drosophila melanogaster, we identified a conserved mutual protection mechanism between CENP-A and HJURP between flies and human cells, where their physical interaction protects each other from being targeted for degradation. Moreover, we showed that HJURP stability is regulated both in vitro and in vivo by the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin E3 ligase. We further demonstrated that CENP-A and APC/C compete for the same binding site on HJURP. Using isogenic breast cancer cell culture progression series, we found that many centromere proteins are progressively overexpressed at the protein level during tumorigenesis. These results led us to hypothesize that overexpression of centromere proteins may cause centromere misregulation and CIN, and contribute to human cancers. To test the idea, we developed a CES (Centromere and kinetochore gene Expression Score) signature that quantitates the mRNA levels of 14 key genes required for centromere structure in cancers. High tumor CES values strongly correlate with increased copy number alterations and mutation frequencies across many cancer types, and prognosticate poor patient survival for many cancers. High CES values also signify high levels of genomic instability that sensitize cancer cells to additional genotoxicity. Indeed, the CES signature forecasts patient response to adjuvant chemo- or radiotherapy for lung and breast cancers. In conclusion, we demonstrate regulation of HJURP by APC/C ubiquitin E3 ligase, mutual protection between the key centromere proteins CENP-A and HJURP, and a mode of misregulation of centromere protein genes in human cancers. We show the efficacy of the CES signature as a potential biomarker to identify patients who likely respond to specific treatments, thus spare the non-responding patients from less effective treatments. These findings are expected to help address the over-treatment problem prevalent in cancer treatments. Our approach validates the critical importance of incorporating basic knowledge of chromosome segregation pathways into cancer research and clinical applications. Note: This abstract was not presented at the meeting. Citation Format: Weiguo Zhang, Jian-Hua Mao, Wei Zhu, Anshu K. Jain, Ke Liu, James B. Brown, Gary H. Karpen. Centromere gene misregulation is a major source of chromosomal instability in human cancers and predicts patient response to specific therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3456. doi:10.1158/1538-7445.AM2017-3456