Cancer Genetics Group, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain.
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, 08908 Barcelona, Spain.
Proc Natl Acad Sci U S A. 2021 Sep 14;118(37). doi: 10.1073/pnas.2024824118.
The MYC axis is disrupted in cancer, predominantly through activation of the MYC family oncogenes but also through inactivation of the MYC partner MAX or of the MAX partner MGA. MGA and MAX are also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small-cell lung cancer (SCLC) cells and carry out genome-wide and proteomics analyses to study the tumor suppressor function of MAX. We find that MAX mutant SCLCs have ASCL1 or NEUROD1 or combined ASCL1/NEUROD1 characteristics and lack MYC transcriptional activity. MAX restitution triggers prodifferentiation expression profiles that shift when MAX and oncogenic MYC are coexpressed. Although ncPRC1.6 can be formed, the lack of MAX restricts global MGA occupancy, selectively driving its recruitment toward E2F6-binding motifs. Conversely, MAX restitution enhances MGA occupancy to repress genes involved in different functions, including stem cell and DNA repair/replication. Collectively, these findings reveal that MAX mutant SCLCs have either ASCL1 or NEUROD1 or combined characteristics and are MYC independent and exhibit deficient ncPRC1.6-mediated gene repression.
MYC 轴在癌症中被打乱，主要是通过 MYC 家族癌基因的激活，但也通过 MYC 伴侣 MAX 或 MAX 伴侣 MGA 的失活。MGA 和 MAX 也是多梳抑制复合物 ncPRC1.6 的成员。在这里，我们使用遗传修饰的 MAX 缺陷型小细胞肺癌 (SCLC) 细胞进行全基因组和蛋白质组学分析，以研究 MAX 的肿瘤抑制功能。我们发现，MAX 突变 SCLC 具有 ASCL1 或 NEUROD1 或联合 ASCL1/NEUROD1 特征，并且缺乏 MYC 转录活性。MAX 恢复会触发分化表达谱的变化，而当 MAX 和致癌性 MYC 共表达时，这种变化会发生。尽管可以形成 ncPRC1.6，但 MAX 的缺乏限制了全局 MGA 占据，选择性地促使其募集到 E2F6 结合基序。相反，MAX 的恢复增强了 MGA 的占据，从而抑制了不同功能的基因，包括干细胞和 DNA 修复/复制。总的来说，这些发现表明，MAX 突变 SCLC 具有 ASCL1 或 NEUROD1 或联合特征，并且是 MYC 非依赖性的，并表现出 ncPRC1.6 介导的基因抑制缺陷。
