MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of atypical Polycomb PRC1.6, E2F and MYC-MAX targets. Similarly, MGA depletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA, E2F6 and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes PRC1.6 subunits. Lastly, we report that MGA loss has also a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F targets mediated by an atypical Polycomb complex containing MGA-MAX dimers.

中文翻译：

---

MGA介导的Polycomb抑制的丧失促进了肿瘤的进展和侵袭性

MGA是MYC网络的转录因子和成员，在广泛的恶性肿瘤中被突变或缺失。作为对肿瘤抑制作用的关键测试，我们使用基于CRISPR的方法灭活了两种非小细胞肺癌小鼠模型中的Mga。MGA的损失显着加速了两种模型中的肿瘤生长，并导致非典型Polycomb PRC1.6，E2F和MYC-MAX靶标的抑制。同样，人肺腺癌细胞株中的MGA耗竭增加了侵袭能力。我们进一步表明，MGA，E2F6和L3MBTL2共同占据了数千个启动子，并且MGA稳定了PRC1.6亚基。最后，我们报道MGA的损失在人类结肠类器官中也具有促生长作用。