HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

• Type of Material: Article
• Authors: Vaishali Pannu, Georgia State University; Padmashree C. G. Rida, Georgia State University; Angela Ogden, Georgia State University; Ravi Chakra Turaga, Georgia State University; Shashikiran Donthamsetty, Georgia State University; Nathan J. Bowen, Clark Atlanta University; Mary Rudd, Emory University; Meenakshi V. Gupta, West Georgia Hospital; Michelle Reid, Emory University; Guilherme Cantuaria, Northside Hospital Cancer Institute; Claire E. Walczak, Indiana University; Ritu Aneja, Georgia State University
• Language: English
• Date: 2015-03-20
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Pannu et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.3475
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 6
• Issue: 8
• Start Page: 6076
• End Page: 6091
• Grant/Funding Information: This study was supported by grants to RA from the National Cancer Institute at the National Institutes of Health (UO1 CA179671, RO1 CA169127).
• Keywords: tumor progression; Life Sciences & Biomedicine; SPINDLE; Cell Biology; HSET; microtubule motor; EXTRA CENTROSOMES; P110 CUX1; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; EXPRESSION; CELL LUNG-CANCER; CHROMOSOMAL INSTABILITY; COLORECTAL-CANCER; Science & Technology; AURORA-B; cell-cycle kinetics; Oncology; centrosome clustering; MYELOID-LEUKEMIA
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cellcycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target.