RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora‐A and BRCA2 in midbody during cytokinesis

Abstract

The oncogene RAS is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora-A and BRCA2 in ovarian cancer cell lines and tumor samples containing RAS mutations. We found that Aurora-A and BRCA2 inversely controlled RAS-associated genomic instability and ovarian tumorigenesis through regulation of cytokinesis and polyploidization. Over-expression of mutated RAS ablated BRCA2 expresson but induced Aurora-A accumulation at the midbody, leading to abnormal cytokinesis and ultimately chromosomal instability via polyploidy in cancer cells. RAS regulates the expression of Aurora-A and BRCA2 through dysregulated protein expression of farnesyl protein transferase β (FTβ and insulin-like growth factor binding protein 3 (IGFBP-3). Our results suggest that the imbalance in expression of Aurora-A and BRCA2 regulates RAS-induced genomic instability and tumorigensis.

Fibrillin-1, induced by Aurora-A but inhibited by BRCA2, promotes ovarian cancer metastasis

“…The serine/threonine kinase Aurora-A (Aur A), a member of Aurora kinase family reported to induce centrosome amplification, chromosomal instability, and transformation in mammalian cells, is amplified in multiple carcinomas, including ovarian cancer [2, 3]. Breast cancer 2, early onset (BRCA2), as a tumor suppressor functioning in DNA damage repair and genomic stability maintenance, has been linked to several types of cancers [4, 5].…”

“…Breast cancer 2, early onset (BRCA2), as a tumor suppressor functioning in DNA damage repair and genomic stability maintenance, has been linked to several types of cancers [4, 5]. Although we and others have reported that Aur A or BRCA2 promotes or inhibits genomic instability and tumorigenesis through the regulation of cell cycle progression, cytokinesis, and polyploidy [2, 6, 7], the data from literatures indicate that Aur A and BRCA2 may also be involved in cancer metastasis. For instances, the pharmacological or RNA interference-mediated inhibition of Aur A blocked cell migration and adhesion by inhibiting the phosphorylation of the cytoskeletal regulatory protein SRC, whereas the enforced expression of Aur A activated SRC to promote cell migration and adhesion [8].…”

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

“…The last direction is quite important, as it causes inevitably genomic instability (59) (Figure 2). K-ras mutation is a major etiological factor of genomic instability (60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(78)(79)(80), which is absolutely necessary for the tumorigenesis process to accelerate.…”

Degradation of Activated K-Ras Orthologue via K-Ras-specific Lysine Residues Is Required for Cytokinesis

“…Furthermore, it has been shown that Ras is activated at the cellular poles during cytokinesis in Dictyostelium (14,31,39,40) and that K-Ras is shown to have an important role in cytokinesis and genome stability in mammalian cells (32,41,42). The findings in Dictyostelium RasG potentially reflect the circumstance of tumorigenesis driven by hyper-activation of K-Ras: the expression of mutated K-Ras not only activates downstream signaling but also induces aneuploidy and promotes tumorigenesis (33, 34, 43, 44).…”

“…Recently, it has been shown that Cdc42, a Rho family GTPase essential for cytokinesis, is down-regulated during mitotic exit, which is required for proper cytokinesis (22,23,32). To assess the functional significance of RasG ubiquitination, we assessed cytokinesis of wild-type-and 4KR-RasG-expressing RasGnull cells using suspension culture where cytokinesis-deficient mutants become multinucleated (20,24,25,33,34).…”