Maia-Silva, Diogo, Schier, Allison C, Skopelitis, Damianos, Kechejian, Vahag, Alpsoy, Aktan, Liverpool, Jynelle, Taatjes, Dylan J, Vakoc, Christopher R (October 2023) Marker-based CRISPR screening reveals a MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma. bioRxiv. (Submitted)
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Abstract
The presence of basal lineage characteristics signifies hyper-aggressive human adenocarcinomas of the breast, bladder, and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor p63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to classical PDAC. Taken together, our comprehensive genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders Investigative techniques and equipment Investigative techniques and equipment > CRISPR-Cas9 diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Vakoc lab School of Biological Sciences > Publications |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 27 October 2023 |
| Date Deposited: | 16 Nov 2023 17:06 |
| Last Modified: | 05 Apr 2024 18:23 |
| PMCID: | PMC10634811 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41311 |
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