What is it about?

Cancer cells are commonly subjected to stress due to intrinsic metabolic changes and the adverse tumor microenvironment. To gain survival advantage, cancer cells produce more of the 78-kilodalton glucose regulated protein GRP78 and hijack its function to promote tumor growth, metastasis, and therapeutic resistance. The discovery that when over-expressed, GRP78 which primarily resides in the endoplasmic reticulum can escape to other cellular compartments to gain new functions represents a paradigm shift. Here, towards understanding how GRP78 regulates the transcription of EGFR, a well-established cancer promoter, we discover that nuclear GRP78 is prominent in cancer and stressed cells and uncover a signal in GRP78 that is critical for its entry into the nucleus. Furthermore, through biochemical, imaging and bioinformatics analysis, we found that nuclear GRP78 can regulate expression of genes and pathways, notably those important for cell migration and invasion, by interacting with and inhibiting the activity of the transcriptional repressor ID2. Our study reveals a new mechanism for cancer cells to respond to stress via transcriptional regulation mediated by nuclear GRP78 to adopt an invasive phenotype.

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Why is it important?

The new findings point to several potential new approaches for cancer treatment, including suppression of EGFR in lung cancer by inhibiting GPR78, or preventing it from binding to ID2. GRP78 could also bind other proteins in the nucleus critical for cancer, thus opening up a new line of research in cancer biology. While the present study analyzed lung cancer cells, GRP78 plays a similar role in various types of cancers, including pancreatic, breast and colon cancer. Furthermore, the discovery that GRP78, a major endoplasmic reticulum protein, can migrate to the nucleus and assume new functions, could also have broad implications across the field of cell biology. This study implies that other proteins that typically reside in one part of the cell could, under stress or other triggers, migrate to another part of the cell and alter cell behavior in multiple ways.


“Seeing GRP78 in the nucleus controlling gene expression is a total surprise. When it comes to the basic mechanisms of cancer cells, this is something novel that to my knowledge, no one has observed before. Another surprise is that the key genes being regulated by GRP78 in the nucleus are mainly involved with cell migration and invasion. In sum, this study reveals a new concept. The protein itself is the soldier that does the job, but now we’re thinking it’s not just about the soldier, but also where the solider is deployed.” Amy S. Lee, Ph.D. University of Southern California School of Medicine

Amy Lee
University of Southern California

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This page is a summary of: ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator, Proceedings of the National Academy of Sciences, July 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2303448120.
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