Abstract
Targeting PI3Kα enhances KMT2D methyltransferase activity to promote ER-mediated transcription.
Major finding: Targeting PI3Kα enhances KMT2D methyltransferase activity to promote ER-mediated transcription.
Mechanism: PI3Kα inhibition promotes KMT2D-mediated recruitment of ER, FOXA1, and PBX1 to chromatin.
Impact: Dual inhibition of PI3K and KMT2D may be more effective than PI3K inhibition alone in ER+ breast cancer.
Activating mutations in PIK3CA (encoding PI3Kα) occur frequently in estrogen receptor (ER)–positive breast cancer, and PI3K signaling promotes breast tumorigenesis. PI3Kα inhibitors have antitumor activity in patients with PIK3CA-mutant ER+ breast cancer, but a compensatory increase in ER-mediated transcription limits the duration of response. Toska and colleagues investigated the mechanisms by which PI3Kα inhibitors promote ER signaling. Chromatin immunoprecipitation sequencing in breast cancer cells revealed that PI3Kα inhibition enhanced ER binding to chromatin and also promoted binding of the transcription factors FOXA1 and PBX1, which were required for PI3Kα inhibitor–mediated ER activation. In breast cancer xenografts, the antitumor activity of the PI3Kα inhibitor BYL719 was enhanced by depletion of FOXA1 or PBX1, further demonstrating that FOXA1 and PBX1 promote ER activation in response to PI3Kα inhibition. PI3Kα inhibition remodeled the chromatin landscape, increasing chromatin accessibility and promoting ER-dependent transcription in BYL719-treated cells and tumor biopsies. BYL719-mediated ER activation was induced by the histone methyltransferase KMT2D, which mono- and dimethylated histone 3 lysine 4 (H3K4me1/2) to promote recruitment of FOXA1, PBX1, and ER to specific chromatin sites. Accordingly, KMT2D depletion reduced the ER, FOXA1, and PBX1 chromatin binding, and increased the antitumor activity of BYL719 in vitro and in vivo, indicating that KMT2D inhibitors might increase the sensitivity to PI3Kα inhibitors in patients with ER+ breast cancer. Mechanistically, PI3K inhibition relieved AKT-dependent phosphorylation of KMT2D at S1331, thereby activating KMT2D and enhancing ER activity. In addition to elucidating a mechanism by which PI3Kα inhibition promotes ER signaling, these findings suggest that KMT2D inhibition may enhance the efficacy of PI3Kα inhibition in patients with ER+ breast cancer.
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