Research Achievement
A research team led by Professor Xiang David Li from The University of Hong Kong (HKU), in collaboration with researchers from Shenzhen Bay Laboratory and Tsinghua University, has developed a chemical inhibitor designed to target the ATAC complex. This complex activates genes associated with tumor development, and its inhibition is proposed as a novel therapeutic approach for non-small cell lung cancer (NSCLC). The research findings have been published in Nature Chemical Biology, and international patent applications have been submitted.
Histone Modifications and the ATAC Complex
Within human cells, DNA is organized around histone proteins, forming chromatin. Chemical modifications on histones regulate gene expression. Histone acetylation acts as an "on" switch for gene activation, a process catalyzed by histone acetyltransferase (HAT) enzyme complexes. The ATAC complex is a type of HAT complex that activates genes involved in cell growth and DNA replication. In cancers like NSCLC, the ATAC complex exhibits increased activity, leading to the activation of cancer-driving genes and contributing to tumor growth. Previous drug development efforts to inhibit ATAC faced challenges due to GCN5, its catalytic subunit, being shared by other essential HAT complexes, potentially causing side effects.
Targeted Inhibition Strategy
To overcome the challenge of selective inhibition, Professor Li's team focused on YEATS2, a protein subunit unique to the ATAC complex. Utilizing structure-guided design, the researchers developed LS-170, an inhibitor that specifically binds to the acetyl-lysine recognition domain of YEATS2. This binding action prevents the ATAC complex from attaching to chromatin, resulting in its displacement from target genomic regions. The displacement leads to a reduction in local histone acetylation and the deactivation of oncogenes in NSCLC.
Efficacy and Broader Implications
In both NSCLC cell lines and animal models, LS-170 demonstrated effectiveness in suppressing tumor growth and metastasis. The YEATS2 gene is frequently amplified across various solid tumors, including lung, ovarian, and pancreatic cancers. This suggests that the targeted inhibition strategy could have broader therapeutic applications beyond lung cancer. This study provides a chemical method to investigate the function of a specific HAT complex and its role in cancer gene expression, potentially informing the development of other complex-specific epigenetic drugs. Professor Li commented that this approach offers new possibilities for highly selective, complex-specific drug development.