Unique role and vulnerability of EP300 KIX domain in small-cell lung cancer
Kim, K.-B.; Kabra, A.; Kim, D.-W.; Xue, Y.; Hou, P.-C.; Zhou, Y.; Miranda, L.; Shi, X.; Bender, T. P.; Bushweller, J. H.; Park, K.-S.
Show abstract
EP300 (E1A binding protein p300) is a versatile transcription co-activator important in cell proliferation and differentiation. The gene EP300 is frequently mutated in diverse cancer types, including small-cell lung cancer (SCLC). While it is widely believed that these mutations result in loss of EP300 function, the impact on SCLC pathogenesis remains largely unknown. Here we demonstrate that mutant EP300 variants lacking histone acetyltransferase (HAT) domain accelerate tumor development in autochthonous mouse models of SCLC. However, unexpectedly, complete knockout of Ep300 suppresses tumor development and inhibits proliferation of both human and mouse SCLC cells. Genetic dissection of EP300 domains identifies kinase-inducible domain (KID)-interacting (KIX) domain, specifically its interaction with transcription factors such as CREB1 and MYB, as the determinant of pro-tumorigenic activity. Blockade of the KIX-mediated protein interactions using a small molecule and a recombinant peptide mimicking the KIX-binding sequences of EP300-interacting partners inhibits the growth of SCLC cells. These findings identify domain-specific roles of EP300 in SCLC and unique vulnerability of the EP300 KIX domain to potential therapeutics.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- USP28 deletion and small molecule inhibition destabilises c-Myc and elicits regression of squamous cell lung carcinoma 96%
- Loss of MGA mediated Polycomb repression promotes tumor progression and invasiveness 95%
- An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma 95%
Similar papers in this journal
- Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression 94%
- CRISPR/Cas9 screen identifies KRAS-induced COX-2 as a driver of immunotherapy resistance in lung cancer 94%
- Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation 93%
Similar papers in this journal
- p53 restoration in small cell lung cancer identifies a latent Cyclophilin-dependent necrosis mechanism 96%
- Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes 95%
- Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells 95%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.