Abstract
mRNA expression of the DLC1 tumor suppressor gene is downregulated in many lung cancers and their derived cell lines, with DLC1 protein levels being low or absent. Although the role of increased EZH2 methyltransferase in cancer is usually attributed to its histone methylation, we unexpectedly observed that post-translational destabilization of DLC1 protein is common and attributable to its methylation by cytoplasmic EZH2, leading to CUL-4A ubiquitin-dependent proteasomal degradation of DLC1. Furthermore, siRNA knockdown of KRAS in several lines increases DLC1 protein, associated with a drastic reduction in cytoplasmic EZH2. Pharmacologic inhibition of EZH2, CUL-4A, or the proteasome can increase the steady-state level of DLC1 protein, whose tumor suppressor activity is further increased by AKT and/or SRC kinase inhibitors, which reverse the direct phosphorylation of DLC1 by these kinases. These rational drug combinations induce potent tumor growth inhibition, with markers of apoptosis and senescence, that is highly dependent on DLC1 protein.
Highlights
MRNA expression of the DLC1 tumor suppressor gene is downregulated in many lung cancers and their derived cell lines, with DLC1 protein levels being low or absent
To be able to analyze other cell lines in subsequent experiments, we screened a panel of non-small cell lung cancer (NSCLC) lines for their expression of DLC1 mRNA and protein under regular growth conditions
The methylation of DLC1 protein induced by EZH2 is potentially reversible, which enables EZH2 inhibitors to increase the half-life of the DLC1 protein and, together with kinase inhibitors that can dephosphorylate and reactivate the tumor suppressor activity of
Summary
MRNA expression of the DLC1 tumor suppressor gene is downregulated in many lung cancers and their derived cell lines, with DLC1 protein levels being low or absent. We initiated the current study by screening for drugs in addition to proteasome inhibitors[15] that might increase DLC1 protein levels, as they could lead to identification of additional vulnerabilities that might increase our understanding of the pathways regulating DLC1 expression and might have therapeutic application This screen unexpectedly determined that the DLC1 protein was stabilized by inhibitors of EZH2, the catalytic component of the polycomb repressor complex 2 (PRC2) that is a predominantly nuclear lysine methyltransferase frequently overexpressed or mutated in cancer[16,17]. The post-translational regulation of DLC1 by cytoplasmic EZH2 differs from its canonical nuclear epigenetic regulation of gene expression by trimethylation of histone H3 on Lysine 27 (H3K27)
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