Combined Menin and EGFR Inhibitors Synergize to Suppress Colorectal Cancer via EGFR-Independent and Calcium-Mediated Repression of SKP2 Transcription
Combined Menin and EGFR Inhibitors Synergize to Suppress Colorectal Cancer via EGFR-Independent and Calcium-Mediated Repression of SKP2 Transcription
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DOI：
10.1158/0008-5472.can-18-2133
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发表时间：
2019-05-01
期刊：
影响因子：
11.2
通讯作者：
Hua, Xianxin
中科院分区：
文献类型：
--
作者：
Katona, Bryson W.;Glynn, Rebecca A.;Hua, Xianxin
Menin是一种核表观遗传调节因子，可以以高度组织特异性的方式促进和抑制肿瘤生长。然而，menin在结直肠癌中的作用仍不清楚。在这里，我们证明了menin在结直肠癌中过表达，并且menin的抑制与EGFR的小分子抑制剂（iEGFR）协同作用，以EGFR非依赖性方式抑制结直肠癌细胞和肿瘤异种移植物。从机制上讲，menin结合了SKP2（一种对结直肠癌生长至关重要的原癌基因）的启动子，并促进了其表达。此外，iEGFR吉非替尼激活内质网钙通道三磷酸肌醇受体3（IP3R3）介导的钙释放，直接结合menin。联合抑制menin和iEGFR诱导的钙释放协同抑制menin介导的SKP2表达和结直肠癌生长。总之，这些发现揭示了menin和iEGFR诱导的IP3R3介导的SKP2转录钙释放的分子融合，并揭示了增强iEGFR疗效以改善结直肠癌治疗的机会。Menin作为SKP2表达的钙响应调节剂和小分子EGFR抑制剂，其诱导钙释放，与Menin抑制协同降低SKP2表达并抑制结肠直肠癌。
Menin is a nuclear epigenetic regulator that can both promote and suppress tumor growth in a highly tissue-specific manner. The role of menin in colorectal cancer, however, remains unclear. Here, we demonstrate that menin was over-expressed in colorectal cancer and that inhibition of menin synergized with small-molecule inhibitors of EGFR (iEGFR) to suppress colorectal cancer cells and tumor xenografts in vivo in an EGFR-independent manner. Mechanistically, menin bound the promoter of SKP2, a pro-oncogenic gene crucial for colorectal cancer growth, and promoted its expression. Moreover, the iEGFR gefitinib activated endoplasmic reticulum calcium channel inositol trisphosphate receptor 3 (IP3R3)-mediated release of calcium, which directly bound menin. Combined inhibition of menin and iEGFR-induced calcium release synergistically suppressed menin-mediated expression of SKP2 and growth of colorectal cancer. Together, these findings uncover a molecular convergence of menin and the iEGFR-induced, IP3R3-mediated calcium release on SKP2 transcription and reveal opportunities to enhance iEGFR efficacy to improve treatments for colorectal cancer.Significance: Menin acts as a calcium-responsive regulator of SKP2 expression, and small molecule EGFR inhibitors, which induce calcium release, synergize with Menin inhibition to reduce SKP2 expression and suppress colorectal cancer.