Study shows how liver cancer hijacks circadian clock machinery inside cells

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Pictured is an artist’s rendering of the circadian clock proteins BMAL1 and CLOCK that influence hepatocellular carcinoma (HCC) cell proliferation. The study shows that in humans, HCC cells rely on BMAL1 and CLOCK for sustained cell growth. Targeting the clock proteins provides a new avenue for developing new cancer therapies. Credit: Julia E. Fletcher-Selway (JEFS Storytelling Arts, Carlsbad, CA)

The most common type of liver cancer, hepatocellular carcinoma (HCC), is already the third leading cause of cancer-related deaths worldwide, and cases are on the rise, both in the US and around the world. the world. While chemotherapy, surgery, and liver transplants can help some patients, targeted treatments for HCC could save millions more lives.

Recent studies have offered clues to a potential target: circadian clock proteins inside cells, which help coordinate changes in the body’s functioning throughout the day. But most of this research only hints at an indirect link between circadian clock function and HCC, for example, the observation that cells collected from liver cancer patients have disrupted circadian rhythms.

Now, a study led by researchers at the USC Keck School of Medicine not only directly links circadian clock proteins to liver cancer, but also shows precisely how cancer cells hijack the circadian clock machinery to divide and spread. The research, recently published in the journal Proceedings of the National Academy of Scienceshe also found that inhibiting key clock proteins can prevent cancer cells from multiplying.

“Previous studies didn’t give us a real idea of ​​how we might use a specific treatment to target processes within liver cancer cells. In this paper, we’re taking the first steps toward that,” said the study’s lead author, Steve A. Kay, Ph.D., University Professor and Provost of Neurology, Biomedical Engineering, and Quantitative Computational Biology at the USC Keck School of Medicine and Director of the USC Michelson Center for Convergent Bioscience.

The research is a collaboration between cell biology experts and physicians at the USC Norris Comprehensive Cancer Center, which is known for its leadership in clinical trials for various types of cancer, including HCC.

“We are very excited to find a new and innovative treatment strategy that may ultimately improve outcomes for patients with liver cancer,” said Heinz-Josef Lenz, MD, professor of medicine and preventive medicine, associate director of clinical research and co-director of the USC Norris Gastrointestinal Cancers Program. “By targeting the circadian clock, we not only target the tumor cells, but also the area around the tumor, which may help increase the efficacy of other targeted treatments.”

disrupting the cell cycle

To elucidate the role of circadian clock proteins in HCC, Kay, Lenz, and their colleagues conducted a series of experiments, using a combination of cell culture, genomic analysis, and animal models.

First, the researchers demonstrated that two key clock proteins, known as CLOCK and BMAL1, are essential for the replication of liver cancer cells in cell culture. When CLOCK and BMAL1 are suppressed, the replication process of cancer cells is disrupted, ultimately leading to cell death or apoptosis. Triggering apoptosis, during which a cell stops dividing and then self-destructs, is the goal of many modern cancer treatments.

Next, the team turned to their toolbox of genomic samples, built from years of research on circadian clock proteins in the body, to better understand the role of CLOCK and BMAL1. Among other findings, they showed that removal of the clock proteins reduced levels of the enzyme Wee1 and increased levels of the enzyme inhibitor P21.

“That’s exactly what you want, because when it comes to cancer cell proliferation, P21 is a brake and Wee1 is an accelerator,” said Kay, who also co-directs the USC Norris Center for Cancer Drug Development. .

Finally, the researchers tested their findings Live. Mice injected with unmodified human liver cancer cells developed large tumors, but those injected with cells engineered to suppress CLOCK and BMAL1 showed little or no tumor growth.

Development of targeted therapies

Understanding how cancer cells hijack circadian clock proteins is a big step in stopping the spread of liver cancer, but researchers have more questions to answer. For example, Kay and her team hope to explore the relationship between the circadian clock protein Wee1 and the P53 gene. The gene helps prevent the growth of tumors in the body, and mutations in P53 have long been linked to an increased risk of several types of cancer.

“We really need to understand that relationship to better identify which patients might benefit most from a therapy that targets CLOCK and BMAL1,” Kay said.

He and his team also hope to start testing experimental drugs that can target CLOCK and BMAL1 in patients with liver cancer. The work is part of a larger body of research by him looking at circadian clock proteins in various types of cancer, including glioblastoma, leukemia and colorectal cancer.

In addition to Kay and Lenz, the other study authors are Meng Qu and Alexander Vu of the USC Keck School of Medicine Department of Neurology; Raymond Wu and Hidekazu Tsukamoto of the Department of Pathology, USC Keck School of Medicine; Guoxin Zhang and Jeremy N. Rich of the University of Pittsburgh Department of Neurology; Han Qu and Zhenyu Jia of the Department of Botany and Plant Sciences at the University of California, Riverside; and Wendong Huang of the Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope National Medical Center.

More information:
Meng Qu et al, Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and the cell cycle, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2214829120

Provided by USC Keck School of Medicine

Citation: Study Shows How Liver Cancer Hijacks Circadian Clock Machinery Inside Cells (Jan 6, 2023) Retrieved Jan 6, 2023 from cancer-hijacks-circadian-clock.html

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