Aurora kinase A mediates c‐Myc's oncogenic effects in hepatocellular carcinoma

Abstract

Dysregulation of c-Myc (Myc) has been shown to contribute to progression of hepatocellular carcinoma, however, the detailed molecular mechanism remains poorly understood. Here, we report that Myc binds to the Aurora kinase A (Aurka) promoter and induces expression of Aurka in HCC cells. Increased expression of Aurka correlates with that of Myc in HCC. Nuclear accumulation of Aurka was confirmed by subcellular protein fractionation and immunoblot experiments in HCC cells. Myc inhibition decreases the nuclear accumulation of Aurka in HCC cells. Also Aurka accumulating in the nucleus up-regulates Myc transcription by binding the Myc promoter containing the highly conserved CCCTCCCCA in the NHE region of the CpG islands. Inhibition of Myc or Aurka diminishes the malignant phenotypes of HCC cells by down-regulating some common target genes. Also Aurka and Myc mediates the effects of each other, at least partially, on proliferation, anchorage-independent soft agar growth, and ATP production. Blocking Aurka in an orthotopic model significantly impairs tumor growth in mice. These results identify a Myc-Aurka feedback loop in which Myc and Aurka regulate expression of each other at the transcriptional level and both play an important role in hepatocarcinogenesis.

Recombinant human bone morphogenetic protein-2 inhibits gastric cancer cell proliferation by inactivating Wnt signaling pathway via c-Myc with aurora kinases

“…For instance, AURKA stimulates telomerase activity by upregulating Myc in human ovarian and breast epithelial cells [43]. Destruction of AURKA or Myc inhibits the malignant phenotypes of hepatocellular carcinoma cells [32]. In agreement with previously published articles, our results showed that there was a direct correlation with c-Myc expression and AURK, and both were suppressed by rhBMP-2 in gastric cancer cells.…”

“…We validated c-Myc expression after treatment with rhBMP-2 by qPCR and western blot assay; we found that c-Myc expression was significantly suppressed by rhBMP-2 treatment in both types of gastric cancer cells. Myc is recognized as a crucial oncogene in many types of human cancers, including gastric cancer [32–34]. Therefore, the downregulation of c-Myc by rhBMP-2 might be responsible for the inhibition of gastric cancer cells.…”

“…A study of AURKA and regulation of the cell cycle in cancer through multiple signal pathways found that AURKA diminished pRb, p53, P21waf1/cip1, and p27cip/kip but increased Plk1, CDC25, CDK1, and cyclin B1 to promote cell cycle progression [35]. Overexpression of AURKA inhibits p53 and p73 levels in cancer cells [32, 36, 37]. AURKA and AURKB are also overexpressed in a variety of human cancers, and the activation of AURKA and AURKB has oncogenic effects [38–42].…”

“…In addition, combination treatment with an rhBMP-2 and AURK inhibitor significantly decreased c-Myc expression in SNU484 and SNU638 cells compared to treatment of the rhBMP-2 or AURK inhibitor alone. Several studies have reported that Myc and AURKA directly regulate each other at the transcriptional level in various cancer cells [32, 43, 44]. For instance, AURKA stimulates telomerase activity by upregulating Myc in human ovarian and breast epithelial cells [43].…”

Combined inhibition of MEK and Aurora A kinase in KRAS/PIK3CA double-mutant colorectal cancer models

“…Though demonstrated in breast cancer models, this concept has important implications given a potential relationship between Aurora A kinase and Myc, as demonstrated in various Myc-driven malignancies including hepatocellular carcinoma and B-cell lymphomas (Den Hollander et al, 2010; Lu et al, 2014). In both tumor types, Myc has been found to induce Aurora A kinase, and thus it may be hypothesized that the more synergistic combination effects demonstrated in select CRC models could be due to MEK inhibitor mediated degradation of c-Myc leading to more robust effects on Aurora A.…”