Impairing Golgin-45 transcription factor activity unleashes malignant secretion in lung cancer

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Abstract

Golgin-45 (G45) is a coiled-coil protein that transits reversibly between the Golgi and nucleus. In the Golgi, G45 serves as a tether for effectors of a pro-tumorigenic secretory program, but its nuclear role remains unclear. Here, we report that, upon entering the nucleus, G45 functions as a basic leucine zipper transcription factor. From genomic mapping, RNA-sequencing, and functional validation studies, we identify G45-binding sites and show that nuclear G45 can function as a transcriptional activator or repressor, a versatility enabled by phase separation into nuclear bodies enriched in transcriptional co-regulators. In lung cancer models, Golgi-docking reinforces, whereas nuclear translocation opposes, pro-tumorigenic activity of G45. Nuclear G45 incorporates into dimeric transcription factors that silence pro-tumorigenic secreted cargos. Epigenetic events in lung cancer degrade nuclear G45 and sequester G45 in the Golgi, which unleashes malignant secretion. Thus, inter-organelle transitions govern a G45-dependent secretory axis that drives lung cancer progression.

Authors

Chao Wu, Abhishek Kumar, Shike Wang, Weina Zhao, Yuanxin Xi, Jing Wang, Abhinav K. Jain, William K. Russell, Hou-fu Guo, Xiaochao Tan, Jonathan M. Kurie