Chemical genetics in Caenorhabditis elegans identifies anticancer compound chaetocin and p300/CBP as modulators of metal response genes

We recently used a genome-wide screen to demonstrate that numr-1/2 is activated by disruption of RNA metabolism. To investigate numr-1/2 regulation and identify modulators of nucleic acid metabolism, we screened over 40,000 compounds and extracts from commercial and natural product libraries for numr-1/2p::GFP activation. Fungal toxin chaetocin was the most potent and least toxic numr-1/2 inducer. RT-qPCR demonstrates that chaetocin induces numr-1/2 and another stress-responsive SR-like protein gene (W03G1.5) in C. elegans over 50-fold within 45 minutes without affecting expression of canonical heat shock, osmotic stress, endoplasmic reticulum stress, mitochondrial stress, or detoxification response genes. Chaetocin does not activate other metal-responsive genes and actually reduces expression of metallothionein gene mtl-2 and fluorescence of mtl-2p::GFP consistent with repression of mtl-2 transcription. Along with a similar HMTase inhibitor from the same fungal origin - Chetomin, and two synthetic S-methyl-products of Chaetocin and Chetomin, respectively, we tested the expression profile at 5h and 12h post treatment at 500 nM concentration in HCT116 colorectal carcinoma cell line. Both S-methyl-products showed no significant activity or any detectable statistically significant changes in expression compared to the vehicle control. The parent compounds induced a number of expression changes consistent with effects on the stress-response genes in HCT116 cells.