Caspase‐14 suppresses GCM1 acetylation and inhibits placental cell differentiation

Glial cell missing 1 (GCM1) transcription factor regulates placental cell fusion into the syncytiotrophoblast. Caspase‐14 is proteolytically activated to mediate filaggrin processing during keratinocyte differentiation. Interestingly, altered expression of nonactivated caspase‐14 proenzyme is associated with tumorigenesis and diabetic retinopathy, suggesting that caspase‐14 may perform physiological functions independently of its protease activity. Here, we performed tandem affinity purification coupled with mass spectrometry analysis to identify caspase‐14 proenzyme as a GCM1‐interacting protein that suppresses GCM1 activity and syncytiotrophoblast differentiation. Immunohistochemistry revealed that caspase‐14 and GCM1 colocalize to placental cytotrophoblast cells at 8 wk of gestation and syncytiotrophoblast layer at term. Further, we demonstrated that caspase‐14 mRNA level is decreased by 40% in placental BeWo cells treated with forskolin (FSK). To the contrary, stimulation of GCM1‐regulated placental cell fusion and human chorionic gonadotropin β (hCGβ) expression by FSK is enhanced by caspase‐14 knockdown. Indeed, GCM1 protein level is increased by 40% in the caspase‐14‐knockdown BeWo cells. Because GCM1 is stabilized by acetylation, we subsequently showed that caspase‐14 impedes the interaction between GCM1 and cAMP response element‐binding protein (CREB)‐binding protein (CBP) to suppress CBP‐mediated acetylation and transcriptional coactivation of GCM1. Therefore, caspase‐14 can suppress placental cell differentiation through down‐regulation of GCM1 activity.—Wu, Y.‐H., Lo, H.‐F., Chen, S.‐H., Chen, H. Caspase‐14 suppresses GCM1 acetylation and inhibits placental cell differentiation. FASEB J. 27, 2818‐2828 (2013). www.fasebj.org