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MAX-mutant small cell lung cancers sustain impaired activities of the MGA-dependent ncPRC1

ABSTRACT: The MYC-axis is disrupted in cancer, mostly by activation of the MYC-oncogenes but also through inactivation of the MYC-partner, MAX, or of the MAX-partner, MGA, both also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small cell lung cancer (SCLC) cells and apply genome wide and proteomics analysis to study the tumor suppressor function of MAX. We find that MAX-mutant SCLCs classify as ASCL1-type and lack MYC-transcriptional activities. MAX-restitution triggers pro-differentiation expression profiles that shift when MAX and oncogenic MYC (HMYC/MAX) are co-expressed. Despite the ncPRC1.6 can be formed, the lack of MAX restricts global MGA-occupancy, selectively driving its recruitment towards E2F6-motifs. Conversely, MAX-restitution enhances MGA-occupancy and global gene repression of genes involved in different functionalities, including stem-cell and DNA repair/replication. Collectively, these findings reveal that MAX-mutant SCLCs have ASCL1-characteristics, are MYC-independent and their oncogenic features include a deficient ncPRC1.6-mediated gene repression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144457 | GEO | 2021/01/18

REPOSITORIES: GEO

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MAX-mutant small cell lung cancers exhibit impaired activities of MGA-dependent ncPRC1.6.

Project description:The MYC axis is commonly disrupted in cancer, mostly by activation of the MYC family of oncogenes, but also by genetic inactivation of MAX, the obligate partner of MYC, and of the MAX partner, MGA, both of which are members of the polycomb repressive complex, ncPRC1.6. While the oncogenic properties of the MYC family have been extensively studied, the tumor suppressor functions of MAX and MGA and the role of the MYC genes in MAX-mutant cells remain unclear. To address these knowledge gaps, we used chromatin immunoprecipitation, RNA-sequencing and mass spectrometry-based proteomic analysis in MAX-restituted and MYC oncogenic-transformed cell lines derived from human small cell lung cancer (SCLC), which is a high-grade neuroendocrine type of lung cancer. We found that MAX-mutant SCLC cells express ASCL1 and ASCL1-dependent targets, implying that these cells belong to the ASCL1-dependent group of SCLCs. In the absence of MAX, even after ectopic overexpression of MYC, we found no recruitment of MYC to the DNA. Furthermore, MAX reconstitution triggered pro-differentiation expression profiles that shifted when MAX and oncogenic MYC were co-expressed. Although ncPRC1.6 could be formed, the lack of MAX restricted global MGA occupancy, selectively driving its recruitment towards E2F6 motifs. Conversely, MAX restitution enhanced MGA occupancy and global gene repression of genes involved in different functions, including stem-cell and DNA repair/replication. Our data reveal that MAX-mutant SCLCs have ASCL1 characteristics, and are MYC-independent, and that their oncogenic features include deficient ncPRC1.6-mediated gene repression.

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