HEF1 is a crucial mediator of the proliferative effects of prostaglandin E₂ on colon cancer cells

Prostaglandin E₂ (PGE₂), one of the downstream products of cyclooxygenase-2 enzymatic activity, promotes colorectal carcinogenesis in part by stimulating cell division. In this study, we define a critical mechanism in this process by showing that the prometastatic adapter protein human enhancer of filamentation 1 (HEF1; NEDD9) links PGE₂ to the cell cycle machinery in colorectal cancer cells. PGE₂ rapidly induced expression of HEF1 mRNA and protein in colorectal cancer cells. HEF1 overexpression elicited the same effects as PGE₂ treatment on cell proliferation, cell cycle progression, and tumor growth. Conversely, HEF1 knockdown suppressed PGE₂-driven cell proliferation and cell cycle progression. Cell cycle alterations involved HEF1 fragmentation as well as co-distribution of HEF1 and cell cycle kinase Aurora A along spindle asters during cell division. Moreover, Aurora A co-immunoprecipitated with HEF1 and was activated by HEF1. Consistent with a role for HEF1 in colorectal carcinogenesis, we found elevated expression of HEF1 expression in 50% of human colorectal cancers examined, relative to paired normal tissues. These findings establish that PGE₂ induces HEF1 expression, which in turn promotes cell cycle progression through its interaction with and activation of Aurora A. Further, they establish that HEF1 is a crucial downstream mediator of PGE ₂ action during colorectal carcinogenesis.