Like subway commuters on a crowded train, cells generally prefer not to be packed in too tightly. In fact, they have set up mechanisms to avoid this, a phenomenon called “contact inhibition.” A hallmark of cancer cells is that they lack this contact inhibition, and instead become pushy, facilitating their spread. Scientific understanding of the mechanism underlying this cell behavior change has had many gaps. A new paper from the lab of Joseph Kissil, PhD, professor of Molecular Medicine at Scripps Research in Florida, provides important new insights. Writing in the journal Cancer Research, Kissil and colleagues offer new details about how the “stop-growth” signal unfurls during cell-to-cell contact, and how disruption of that “stop-growth” signal can promote cancer. Healthy cells and developing organs “know” when they should grow and when they should stop growing, based on multiple signaling molecules. A key player is a protein called YAP, a regulator of gene expression. YAP is a major effector of a pathway referred to as the Hippo pathway, so named after geneticists discovered that mutations to the HPO gene produced lumpy, hippo-like tissue overgrowth in fruit fly models.
These signals are transmitted by YAP and the Hippo pathway. Tracing out those signals is not only central to understanding our basic biology, but to finding new ways to attack cancers with precision therapies. Increasing cell density normally activates a change in cell signaling. It does this via an elevation of protein involved in initiating contact inhibition, p27Kip1. But a disrupted Hippo pathway interferes with normal YAP behavior and blocks the expected p27 surge. The team was surprised to find YAP in the uncharacteristic role of shutting down gene transcription. Previous studies suggested that YAP is an activator of genes that promote cell growth. The reality proved to be much more complex. In the end, like a broken down subway line, disruption of the Hippo pathway at any point can redirect the cell’s behavior, away from contact inhibition. The discovery of YAP’s dual role as both promotor and repressor of gene transcription provides important information in the efforts to make cancer drugs that act on YAP. Targeting YAP in cancer, is somehow difficult since it is to targeting its function as an activator of cancer, but now scientists must also need to consider its suppressive functions, as well.
Finding the players that both interact with YAP and have a functional role in promoting cancer growth required use of a genome-wide bioinformatics technique called ChIP-seq. The work involved collaboration with the labs of Matthew Pipkin, PhD, of Scripps Research in Florida, and Michael Kareta, PhD, of Sanford Research in Sioux Falls, South Dakota. They used ChIP-seq to map the overlapping relationships of the YAP-linked genes, which number in the thousands. They worked specifically in human myelin-forming Schwann cells, but the findings should apply to other cancers. The team looked at YAP in the context of cell crowding. They learned that YAP’s role involves recruitment of other interacting proteins that include a transcription factor called YY1 (also known as Yin-Yang 1), the protein metil-transferase EZH2 and a nuclear protein complex called PRC2. Those will also be important to study further, as well as the interaction of these players in the context of cancer drug resistance. Indeed, last week an indipendent team from the Huazhong University of Science and Technology of Wuhan, identified CDK5 protein kinase as a new member of Hippo pathway in lung cancer progression and radioresistance.
They identified TAZ, a component of the Hippo pathway, as a critical downstream effector of CDK5. Loss of CDK5 downregulated TAZ expression and attenuates Hippo signaling activation. Their results illustrate that CDK5 activates Hippo signaling via TAZ to participate in tumorigenesis and radioresistance, suggesting that CDK5 may be a promising radiosensitization target for the treatment of lung cancer. They results strenghten what Dr. Kissel stated about cancer drug resistance. Elucidating all the elements composing this signaling pathway would result in a better understanding of alternative mechanisms about how cancer cells elude chemo and radiotherapy.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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