| First Author | Kim M | Year | 2016 |
| Journal | Cell Rep | Volume | 17 |
| Issue | 1 | Pages | 275-288 |
| PubMed ID | 27681437 | Mgi Jnum | J:240566 |
| Mgi Id | MGI:5887170 | Doi | 10.1016/j.celrep.2016.09.003 |
| Citation | Kim M, et al. (2016) Loss of HDAC-Mediated Repression and Gain of NF-kappaB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer. Cell Rep 17(1):275-88 |
| abstractText | ARID1A is frequently mutated in ovarian clear cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here, we established an in vitro model of OCCC by introducing ARID1A knockdown and mutant PIK3CA into a normal human ovarian epithelial cell line, resulting in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while the PIK3CA mutation releases RelA from IkappaB, leading to cytokine gene activation. We show that an NF-kappaB inhibitor partly attenuates the proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and in a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC and suggests that NF-kappaB inhibition could be a potential therapeutic option. |
