Schematic depicting the molecular mechanism through which AMPK epigenetically inhibits lung cancer metastasis [IMAGE: DR. DONG YING]

Lung cancer is highly susceptible to metastasis. Epithelial to mesenchymal transition (EMT) has been implicated as a driver in the dissemination of cancer cells. During EMT, the chromatin landscape is highly changed. Epithelial genes were stably inhibited (marked by H3K27me2/3, H3K9me2/3 and DNA methylation) from an active state, and vice versa to activate mesenchymal genes. Therefore, targeting epigenetic modification is an effective strategy to overcome tumor metastasis.

In a study published in Signal Transduction and Targeted Therapy (STTT) on March 6, a team of researchers led by Li Jia from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences (CAS), in collaboration with Zang Yi from Lingang Laboratory and Shi Hong from Shanghai Pulmonary Hospital, provided mechanistic insights into the AMP-activated protein kinase (AMPK) epigenetically suppressing cancer metastasis via downregulating H3K9me2.

Researchers found that AMPK activation could epigenetically relieve the H3K9me2 mediated silencing of epithelial genes and inhibit lung cancer metastasis. Mechanistically, they identified PHD finger protein 2 (PHF2), a Jumonji C domain-containing histone-lysine demethylase (KDM) that removed H3K9me2, as a direct phosphorylation substrate of AMPK. AMPK phosphorylated PHF2 at S655 to enhance its histone demethylase activity and to trigger epigenetic reprogramming of epithelial genes, thus suppressing lung cancer metastasis. Consistent with these results, the AMPK activator metformin was demonstrated to inhibit lung cancer metastasis via the AMPK-PHF2 axis. Clinically, a higher PHF2-S655 phosphorylation level correlated with better survival in lung cancer patients.

Together, these findings demonstrate a mechanism of AMPK downregulating H3K9me2 modification and provide new insights marking PHF2 as a potential epigenetic target in lung cancer metastasis. Thereby the research promotes the clinical application of metformin to suppressing tumor development.

For more information, please contact:

Diao Wentong

E-mail: diaowentong@simm.ac.cn

Shanghai Institute of Materia Medica (SIMM),

Chinese Academy of Sciences

Source: Shanghai Institute of Materia Medica (SIMM),

Chinese Academy of Sciences