INVOLVEMENT OF THE TRANSCRIPTION FACTOR MYRF IN SIGNALING FROM THE ENDOPLASMIC RETICULUM TO THE NUCLEUS IN PANCREATIC CANCER

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death worldwide. One reason for the poor prognosis is the high intra-tumor heterogeneity, with the coexistence of well- and poorly-differentiated cells in virtually all tumor cases. Thus, a better characterization of the circuitries regulating PDAC cell differentiation is required. We found that MYRF, a poorly characterized transcription factor, is selectively expressed in well-differentiated PDAC cell lines. MYRF is synthetized as an endoplasmic reticulum (ER) membrane protein and self-cleaves after trimerization, releasing the N-terminal trimer that translocates into the nucleus and regulates transcription. We generated MYRF-KO PDAC cells and combined transcriptomic profiles and analyses of MYRF genomic occupancy to study its function. We retrieved the MYRF DNA binding motif from our ChIP-sequencing data and demonstrated that MYRF capability to bind this sequence and activate transcription is strictly dependent on its trimerization. MYRF deletion resulted in the downregulation of cell replication-related genes and upregulation of ER stress-related genes. Consistently, MYRF loss resulted in an altered ER morphology and function, probably as a result of the overexpression of membrane and secreted proteins with complex folding, such as cysteine rich and highly glycosylated proteins. Additionally, we found that MYRF creates a feed-forward loop with the transcription factors FOS and FOSB. In doing so, MYRF directly regulates the expression of these two transcription factors that in turn cooperate to generate the MYRF transcriptional outcome. In conclusion, this work points to a role for MYRF as a key player in the communication between ER and nucleus, working as a sensor of proper ER function. MYRF appears to license cells for DNA replication and concomitantly to serve as a guardian against ER overload in highly secretory cancer cells.