Hepatocellular carcinoma (HCC), the most common form of liver cancer, has become the third deadliest cancer worldwide. As the efficacy and objective response rate of current first-line treatments for advanced HCC are still far from satisfying, new therapies are to be developed to overcome the unmet needs in HCC.

The circadian clock is an evolutionarily conserved mechanism mediating the coordination of behavior and physiological processes with the day-night cycles. The molecular clock centered on the transcription factor BMAL1 and its partner CLOCK (BMAL1::CLOCK) establishes rhythmic expression of many protein-coding genes across mammalian genomes, thereby gating critical physiologies, including sleep, feeding, hormone secretion, metabolism, and immune responses.

The liver represents a hub for circadian regulation – most hepatic functions are under clock control. Recent studies have hinted a role of the clock in HCC development: circadian rhythms are frequently dysregulated in HCC samples; and disrupted circadian clock may lead to spontaneous HCC development. But these studies are largely descriptive – the molecular functions of the clock components implicated in HCC pathogenesis are still enigmatic.

On January 3rd 2023, Dr. Meng Qu, in collaboration with Dr. Steve A. Kay at the University of Southern California, published a research article entitled “Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle” on Proceedings of the National Academy of Sciences of the United States of America. The study sheds light on the cellular and molecular impact of clock proteins for maintaining HCC oncogenesis, providing proof-of-principle for the development of cancer therapy based on circadian clock modulation.

The study has integrated analyses of cell biology, genomics and animal tumor models. First, the authors showed that HCC cells rely on the master circadian clock transcription factors, BMAL1 and CLOCK, for sustained cell growth. When BMAL1 and CLOCK are downregulated, cancer cells’ proliferation rate was substantially reduced – ultimately causing apoptosis. Next, the researchers tested their findings in vivo in HCC xenograft models. Mice injected with unmodified human HCC cells grew large tumors, while those injected with cells modified to suppress CLOCK and BMAL1 showed little to no tumor growth. Finally, the researchers showed that eliminating the clock proteins caused downregulation of the cell cycle kinase WEE1 and upregulation of the cyclin-dependent kinase inhibitor p21. Dysregulation of WEE1 and p21 cooperatively contribute to inhibited growth of tumor cells.

“We are excited to identify a novel potential target for liver cancer treatment.” said Dr. Meng Qu, serving as a ZJU100 Young Professor at Zhejiang University. “Therapeutics targeting the molecular clock has strong potential to be explored either as monotherapy or in combination with current liver cancer therapies.”

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

Link to full-text article: https://www.pnas.org/doi/10.1073/pnas.2214829120

Dr. Meng Qu lab at ZJU: https://person.zju.edu.cn/en/mengqu_international