PNAS: revealing the mechanism by which hepatoma cells hijack circadian clock proteins for proliferation and spread

Hepatocellular carcinoma (HCC), the most common type of liver cancer, has become the third leading cause of cancer-related death worldwide, and HCC cases are increasing
in the United States and worldwide.
While chemotherapy, surgery, and liver transplants can help some patients, targeted therapies targeting HCC could save millions of lives
.

Recent research has provided clues
about a potential target --- intracellular circadian clock proteins, which help coordinate the --- of changes in body functions throughout the day.
But most of these studies only hint at an indirect link between circadian clock function and HCC, such as observing disruption of circadian rhythms in cells taken from liver cancer patients
.

Now, in a new study, researchers from the University of Southern California, the University of California, Riverside, the University of Pittsburgh, and the Fourth Affiliated Hospital of Zhejiang University School of Medicine in China have not only directly linked circadian clock proteins to liver cancer, but also precisely shown how cancer cells hijack the circadian clock mechanism to divide and spread
.
They also found that inhibiting key clock proteins can stop cancer cells from proliferating
.
The results of the study were published online in the journal PNAS on January 3, 2023, in the paper "Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle"
.

Corresponding author Steve A.
Kay, Ph.
D.
, professor of neurology at the Keck School of Medicine at the University of Southern California, said, "Early research didn't really give us a good grasp of how to use a specific treatment to target processes
within liver cancer cells.
In this paper, we take the first step
in this direction.
”

Co-author Dr.
Heinz-Josef Lenz, associate director of clinical research at the University of Southern California Norris Comprehensive Cancer Center, said, "We are very excited to find an innovative treatment strategy that may ultimately improve outcomes for liver cancer patients
.
By targeting the circadian clock, we target not only tumor cells, but also the area around the tumor, which can help improve the efficacy
of other targeted therapies.
”

Interfere with the cell cycle

To elucidate the role of 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, they found that two key clock proteins, CLOCK and BMAL1, are essential
for replication of hepatoma cells in cell cultures.
When CLOCK and BMAL1 are inhibited, the replication process of hepatoma cells is disturbed—eventually leading to apoptosis
.
Triggering apoptosis and then self-destruction is the goal of
many modern cancer treatments.

Next, based on years of research on circadian clock proteins in vivo, they used their toolbox of genomic samples to further understand the role of
CLOCK and BMAL1.
They found that clearing these two clock proteins lowered levels of the enzyme Wee1, increasing levels of P21, an inhibitor of this enzyme
.

Downregulation of Bmal1/Clock activates apoptosis and G2/M phase cell cycle arrest
.
Image from PNAS, 2022, doi:10.
1073/pnas.
2214829120
.

"That's exactly what we want, because when it comes to cancer cell proliferation, P21 is a brake and Wee1 is a gas pedal
," Kay said.
”

Finally, they tested their findings
in vivo.
Mice injected with unmodified human hepatoma cells developed larger tumors, but mice injected with human hepatoma cells that were genetically modified to inhibit CLOCK and BMAL1 had little tumor growth
.

Development of targeted therapies

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

"We really need to understand this relationship in order to better determine which patients might benefit most
from targeted therapies targeting CLOCK and BMAL1," Kay said.
”

He and his team also hope to begin testing experimental drugs
that target CLOCK and BMAL1 in liver cancer patients.
The work is part of
a larger study to analyze clock proteins in several types of cancer, including glioblastoma, leukemia, and colorectal cancer.
(Biovalley Bioon.
com)

Resources:

1.
Meng Qu et al.
 Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle.
PNAS, 2022, doi:10.
1073/pnas.
2214829120.

2.
Study shows how liver cancer hijacks circadian clock machinery inside cells

https://medicalxpress.
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