Regulation of AURKC expression by CpG island methylation in human cancer cells

Abstract

AURKC, a member of the Aurora kinase gene family, is highly expressed in testis but is either moderately expressed or repressed in most somatic cells. Varying expression of AURKC has been observed in human cancers, but the underlying mechanisms of differential expression have been investigated only to a limited extent. We investigated the role of promoter CpG methylation in the regulation of AURKC gene expression in human cancer cells, in relation to a recently reported AURKC transcription repressor PLZF/ZBTB16, implicated in transformation and tumorigenesis. AURKC and PLZF/ZBTB16 expression profiles were investigated in reference to CpG methylation status on the AURKC promoter experimentally, and also in The Cancer Genome Atlas (TCGA) dataset involving multiple cancer types. AURKC promoter showed dense to moderate hypermethylation correlating with low to moderate expression of the gene in normal somatic cells and cancer cell lines, while testis with high expression revealed marked hypo-methylation. Treatment with the demethylating agent, 5-aza-dC, but not the histone deacetylase (HDAC) inhibitor, TSA, led to elevated expression in cancer cell lines, indicating that promoter DNA methylation negatively regulates AURKC expression. High expression of PLZF in PLZF-transfected cells treated with 5-aza-dC only partially repressed expression of AURKC despite 5-aza-dC also inducing elevated PLZF expression. Analyses of the TCGA data showed differential expression of AURKC in multiple cancer types and stronger correlation of AURKC expression with CpG methylation compared to PLZF levels. These findings demonstrate that differential promoter CpG methylation is an important mechanism regulating AURKC expression in cancer cells.

Aurora-C Interactions with Survivin and INCENP Reveal Shared and Distinct Features Compared with Aurora-B Chromosome Passenger Protein Complex

“…The findings that Aurora-C expression is elevated in multiple human cancers indicates a functional role for the kinase in adult somatic tissues and makes it imperative that the molecular details of Aurora-C interactions with the CPC components and the functional consequences of Aurora-C over expression in cancer cells be well elucidated. It is relevant in this context that we have recently reported transcriptional down-regulation of AURKC locus due to hyper-methylation of CpG islands in the promoter to be primarily responsible for low expression of Aurora-C in adult somatic tissues and cell lines in vitro [ 32 ]. Our study further revealed that CpG hypo-methylation besides down-regulation of the previously published transcriptional repressor PLZF/ZBTB16 [ 33 ] is associated with elevated expression of Aurora-C in human cancer cells, also validated in The Cancer Genome Atlas (TCGA) data set across different human cancers.…”

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

“…Differentially from AURKA and AURKB, Aurora kinase C (AURKC) is limited to cells that undergo meiosis (sperm and oocyte). This kinase is located on human chromosome 19q13.43, regulated by promoter methylation and when expressed in germ cells, can undergo alternative splicing resulting in three protein variants [ 561 , 562 , 563 ]. As the major enzymatic component of the CPC during meiosis, it plays a specific role during human female meiosis and preimplantation embryo development [ 564 ].…”

G2/M inhibitors as pharmacotherapeutic opportunities for glioblastoma: the old, the new, and the future

“…In terms of their role as mitotic regulators, deletion of AURKs could lead to cell division failure and embryonic development impairment. Increased expression or gene amplification of AURKs has been described in numerous cancers 158 , including breast 159,160 , ovarian 161,162 , gastric/gastrointestinal 163,164 , colorectal 165,166 , lung 167,168 , cervical 169,170 , prostate 160,171,172 , oral 173,174 , AML 175,176 , and glioma 177,178 . Importantly, in glioma tumors, AURKA and AURKB expression increases with tumor grade, 179-182 , and is significantly associated with GBM poorer patient survival 183-185 .…”