How a Rogue Gene Drives Liver Cancer by Disrupting Fat Metabolism

Liver cancer remains one of the most deadly cancers worldwide, especially in its advanced stages where treatment options are limited. While well-known risk factors such as viral hepatitis, alcohol consumption, and obesity contribute to the development of hepatocellular carcinoma (HCC), recent research has uncovered deeper biological mechanisms fueling tumor growth.

A groundbreaking study led by Professor Jiangwen Zhang from The University of Hong Kong has identified a key genetic player, VPS72, which promotes liver cancer by interfering with the normal regulation of fat metabolism and gene activity within liver cells. Published in Advanced Science, this research sheds light on the complex interactions between genetics and metabolism in cancer progression.

The liver’s primary role as the body’s metabolic hub involves balancing fat synthesis and breakdown. In healthy individuals, this process is tightly controlled. However, in HCC, liver cells begin to accumulate excess fat droplets, which fuel tumor expansion. This abnormal fat buildup is mainly driven by the hyperactivation of the mTORC1 pathway, a molecular switch that stimulates fat-generating genes and enhances cancer cell growth.

Professor Zhang’s team discovered that VPS72, a gene involved in DNA packaging, is excessively active—increasingly present in over half of HCC patients. This overactivity correlates with worse survival outcomes. VPS72 influences gene expression by modifying how DNA interacts with certain proteins, which in turn affects other genes involved in cancer suppression and fat metabolism.

Specifically, VPS72 adds chemical tags to the promoter region of the ATF3 gene, a protective gene that normally prevents unchecked cancer growth. This tagging suppresses ATF3, leading to the overactivation of the mTORC1 pathway. The overactive pathway then boosts the production of fats within cancer cells, providing them with energy and structural components necessary for rapid growth.

In essence, VPS72 acts as a rogue conductor: it silences protective genetic programs, stimulates cancer-promoting pathways, and causes excessive fat accumulation in liver cells—creating an ideal environment for tumor development.

These discoveries open new avenues for targeted therapies. One possibility is to develop drugs that block VPS72’s interaction with DNA or associated proteins, potentially halting its cancer-promoting effects. Additionally, existing drugs that inhibit mTORC1 could be repurposed to treat liver cancers exhibiting high VPS72 activity. By targeting this genetic and metabolic axis, researchers aim to halt or slow tumor progression.

"Our research indicates that VPS72 influences both gene regulation and fat metabolism, making it a pivotal factor in liver cancer development," said Professor Zhang. "Targeting this gene could lead to more effective, tailored treatments for patients with HCC."

This study underscores the critical link between genetic control, metabolic processes, and cancer, highlighting the potential for therapies that disrupt cancer’s metabolic dependencies and genetic drivers.