A team of Johns Hopkins Bloomberg School of Public Health researchers has discovered large droplets of proteins known as condensates near inactive chromosome regions within the cell nucleus that are a feature of some cancer cells and may hold clues for better anticancer strategies.
Condensates have emerged as important features of cell biology and as potential therapeutic targets for cancers, neurodegenerative disorders, and other conditions. Much attention has been given to condensates that activate gene transcription, but the role of condensates with other functions is less clear.
The focus of the study was the TEAD1 protein, an important gene regulator that helps drive cell proliferation. TEAD1 has been implicated in multiple cancer types, including ovarian and breast cancers. The researchers discovered condensates that appear to store excess TEAD1 where it cannot activate genes but is available for later use.
The findings were published online June 11 in Nature Cell Biology.
“We’ve known that cancer-driving gene regulators can get so overactive that they become toxic to the cell, trigger programmed cell death, or otherwise stop cell division,” says study senior author Danfeng Cai , PhD, assistant professor in the Bloomberg School’s Department of Biochemistry and Molecular Biology. “These newly discovered condensates might be the cell’s way of regulating the supply of TEAD1 to keep its activity in the optimal range over the long term.”
Studies in recent years by Cai and others found that some other gene regulators gather in small condensates at active regions of chromosomes, where they work with partner proteins to control gene expression; some of these are known to be associated with cancer. In the new study, the researchers looked for TEAD1 condensates in cells derived from patients with renal cell carcinoma, a kidney cancer that can have worse outcomes for patients when TEAD1 protein levels in tumor cells are high.
The researchers found that the cells with high levels of TEAD1 had two types of TEAD1 condensate: small ones, similar to known gene-regulating condensates, in which TEAD1 is actively driving gene activity and, unexpectedly, the larger prominent condensates with little or no gene activity.
The newly discovered condensates are about 40 times larger than the TEAD1-active condensates. They are missing TEAD1’s partner proteins and are clustered at inactive areas of chromosomes in the cell nucleus. Instead of being hubs of activity, the newly discovered condensates appear to function as storage units that help regulate and buffer the supply of this gene-activating protein.
The team observed similar large TEAD1 condensates in some cells from other cancers including melanoma and breast cancer. When they took cells with normal levels of TEAD1 and increased the TEAD1 protein levels, the same large condensates formed—implying that this may be a general mechanism in cell biology, related to the amount of TEAD1 present rather than being unique to cancer cells.
The team found that the condensates formed around the chromosomal centers due to specific DNA sequences in those regions that TEAD1 binds to.
Cai’s team found that disrupting the large TEAD1 condensates in the tumor cells led to increased target gene activity. This finding suggests that the large condensates serve as storage units that effectively keep TEAD1 away from the parts of the genome where it could otherwise drive cell growth, possibly acting as a check on TEAD1 driving toxic levels of cell growth, while keeping a supply of the protein for later use if conditions change.
Researchers have begun to consider condensates as potential treatment targets in various cancers, with the assumption that disrupting them would hinder cancer-promoting gene activity. These findings suggest this may not always be the case.
“One suggestion of these findings is that it might be inadvisable to indiscriminately target TEAD1 condensates in cancer cells, since there are different kinds of condensates with distinct functions,” says Cai. “This is just the first study of what I think will be many on these larger TEAD1 condensates.”
Cai says that the work suggests a potential new approach for cancer therapies to target TEAD1 activity: use or mimic the TEAD1-binding sequences that the large condensates form around to remove or sequester TEAD1 proteins in cancer cells. She adds that another possibility, though so far untested in experiments, would be to disrupt the large TEAD1 condensates so that the excess TEAD1 drives growth gene activation high enough to cause toxic effects, leading to reduced tumor-cell survival.
“ TEAD1 Condensates Are Transcriptionally Inactive Storage Sites on the Pericentromeric Heterochromatin in Cancer Cells ” was co-authored by Yiran Wang, Jindayi Liang, Kimberly Lange, Justin Demmerle, Eleanor Liu, Ethan Black, Britney Jiayu He, Christopher Ricketts, Shawn Yoshida, Shasha Chong, W. Marston Linehan, Jennifer Kavran, Chongzhi Zang, and Danfeng Cai.
Support for the research was provided by the U.S. Department of Defense Kidney Cancer Idea Development Award (W81XWH2210900), the National Institutes of Health (T32GM080189, T32CA009110, R35GM156573, R35GM142837, R35GM133712), Johns Hopkins University Catalyst Award, the National Science Foundation Graduate Research Fellowship Program (DGE-1745301), the Pew-Stewart Scholar for Cancer Research Award, the Searle Scholar Award, the Merkin Innovation Seed Grant, the Mallinckrodt Research Grant, the Margaret E. Early Medical Research Trust Grants, and the Alex’s Lemonade Stand Foundation Innovation Grant (1260879).
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