Abstract
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.
Keywords:
MAX; MGA; SCLC; ncPRC1.6; tumor suppressor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Proliferation
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Gene Expression Regulation, Neoplastic*
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Polycomb-Group Proteins / genetics
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Polycomb-Group Proteins / metabolism*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Small Cell Lung Carcinoma / genetics
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Small Cell Lung Carcinoma / metabolism
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Small Cell Lung Carcinoma / pathology*
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Tumor Cells, Cultured
Substances
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ASCL1 protein, human
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers, Tumor
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Cell Cycle Proteins
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MAX protein, human
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MGA protein, human
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MYC protein, human
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NEUROD1 protein, human
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PRC1 protein, human
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Polycomb-Group Proteins
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Proto-Oncogene Proteins c-myc