Fig. 6

The attenuation of the MEK/ERK pathway leads to a loss of enhancer activity at ARID1A-bound enhancers. Upon treatment with 20 nM trametinib for 24 h, the occupancy of JUND was reduced at the potential enhancers identified (a). Moreover, the same treatment also leads to the reduction of ARID1A occupancy and a loss of the H3K27ac mark on these enhancers (b, c). ChIP was carried out in biological triplicates and qRT-PCRs were run in technical duplicates. The dotted lines represent the average ChIP-qPCR signal for the negative control IgG. Error bars represent the standard deviation between three biological replicates. Significance was calculated using unpaired t test, *p < 0.05, **p < 0.01, ***p < 0.001. In summary, we show that the loss of ARID1A has context-dependent functions in colorectal cancer. Mathur et al. describe that in a wild-type background, the loss of ARID1A is tumor suppressive and leads to the formation of invasive adenocarcinomas. This function is mediated through control of enhancer activity wherein there is a loss of the active H3K27ac mark upon the loss of ARID1A [21]. We show that in colorectal cancer cells which harbor KRAS mutations, ARID1A has a tumor-supporting function by facilitating transcription at enhancers downstream of the MEK/ERK pathway also partially through the placement of the H3K27ac mark (d). In the first case, synthetic lethal targets described in the literature may provide potential therapeutic targets [22, 26, 51,52,53,54]. In the case described here, targeting the BAF complex itself using PROTACS could be an option