Prostate cancer (PCa) remains a leading cause of cancer death in men worldwide. Although patients with localized tumors have favorable outcomes, the 5-year survival for metastatic patients is extremely poor. Therefore, it is of great interest to identify the mechanism driving PCa metastasis.

The histone H3K36 methyltransferase SETD2 is frequently mutated or deleted in a variety of human tumors, such as clear cell renal cell carcinoma (ccRCC), glioma, colorectal cancer, and PCa. Nevertheless, the role of SETD2 loss in oncogenesis remains largely undefined.

It has long been observed that the level of SETD2-mediated H3K36me3 showed a significant inverse correlation with that of EZH2-catalyzed H3K27me3. However, it remains unclear how the interplay between SETD2 and EZH2 is achieved and what is the pathological implications.

In a study published in Cancer Cell on July 2, Dr. QIN Jun's group from Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS), and the collaborators, revealed that H3K36 methyltransferase SETD2 curtails the level of EZH2 to inhibit prostate cancer metastasis by sensing extracellular energy states.

By utilizing genetically engineered mouse models (GEMs) and public data set, the researchers found that SETD2 loss potentiated PCa metastasis. Mechanistic studies showed that SETD2-mediated EZH2 methylation at K735 residue facilitates EZH2 destruction, and prevents the cells transforming into a high H3K27me3 chromatin state to develop full-blown metastatic PCa. Furthermore, they used EZH2-floxed or endogenous K735R mutation mice to prove that the function of SETD2 in PCa is largely dependent on the methylation of EZH2 at K735.

Besides, the researchers found a patient-derived hotspot mutation SETD2-R1523 in human cancers database. Cancer associated SETD2 hotspot mutation at R1523 residue disrupted the interaction and methylation of EZH2 to drive tumor progression in H3K36 methyltransferase independent manner.

They further indicated that AMPK signaling regulates SETD2 expression, suggesting that the SETD2-EZH2 axis translates metabolic cues to alter cellular chromatin state. This finding is of translational interest as metformin may inhibit metastasis caused by SETD2 downregulation.

Together, these results demonstrate that the SETD2-EZH2 axis integrates metabolic and epigenetic signaling to restrict PCa metastasis.

Schematic illustration of the proposed model for SETD2 in PCa metastasis. (Image by Dr. QIN Jun's group)