‘Terminator’ protein halts cancer-causing cellular processes

Essential processes in mammalian cells are controlled by proteins called transcription factors. For example, the transcription factor HIF-1 is triggered by a low-oxygen situation to cause the cell to adapt to decreased oxygen.

Transcription factors operate in healthy cells, but cancer cells can co-opt transcription factors such as HIF-1 into promoting tumor growth.

New research from the lab of Hening Lin, professor of chemistry and chemical biology in the College of Arts and Sciences, finds that a protein called TiPARP acts as a terminator for several cancer-causing transcription factors, including HIF-1, which is implicated in many cancers, including breast cancer. The research demonstrates that TiPARP, therefore, is a tumor suppressor.

The paper “TiPARP Forms Nuclear Condensates to Degrade HIF-1α and Suppress Tumorigenesis,” published in PNAS, establishes TiPARP as a turning-off mechanism for several important transcription factors—including HIF-1, C0-Myc and estrogen receptor—and shows how TiPARP itself is degraded during this process. The study also shows the mechanism through which TiPARP terminates these factors, another new discovery.

Co-authors are graduate student Lu Zhang; former postdoctoral fellow Ji Cao; and Longying Dong, former director of the Immunopathology Research and Development Laboratory in the College of Veterinary Medicine’s Department of Biomedical Sciences.

HIF-1 is important for cancer because a lot of tumors thrive in low-oxygen conditions, said Lin, a Howard Hughes Medical Institute Investigator and corresponding author of the paper.

“For these tumors to survive, they have to rely on HIF-1,” Lin said. “TiPARP is a terminator of HIF-1. Therefore, if you can activate TiPARP, then you can suppress [tumor growth].”

Lin and co-authors are also excited by the discovery of the mechanism through which TiPARP brings about the termination of HIF-1 and other transcription factors. This mechanism, called “liquid-liquid phase separation” or “phase condensation,” is a topic of great interest in biology.

Imagine drops of vinegar in oil: The vinegar forms distinct droplets suspended in the more viscous oil.

Similarly, when TiPARP is activated in a cell nucleus, it forms the so-called “phase separation” that recruits HIF-1-alpha and HUWE1 (an ubiquitin protein ligase) in the cell nucleus. This starts a process through which HIF-1-alpha and TiPARP both deactivate and degrade.

Through phase separation, TiPARP terminates not just HIF-1 but several different transcription factors implicated in different types of cancer, Lin said.

In fact, TiPARP may already be at work in Tamoxifen, a widely used breast cancer drug. Lin thinks Tamoxifen, which successfully treats estrogen receptor-positive breast cancers, works because TiPARP is actively terminating estrogen receptor, HIF-1 and c-Myc in tumors.

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