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Published on: October 27, 2014
MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive
Paula Llabata1, Manuel Torres-Diz2, Antonio Gomez3
1Cancer Genetics Group, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain.
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.
Insights
MAX protein loss in small-cell lung cancer (SCLC) leads to specific cell identities and impaired gene repression. Restoring MAX promotes differentiation but is altered by MYC oncogene coexpression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The MYC signaling pathway is frequently dysregulated in various cancers.
- MAX and MGA are tumor suppressors that partner with MYC and are involved in the ncPRC1.6 complex.
- MAX deficiency contributes to small-cell lung cancer (SCLC) development and progression.
Purpose of the Study:
- To investigate the tumor suppressor role of MAX in SCLC.
- To understand the molecular mechanisms underlying MAX deficiency in SCLC.
- To explore the interplay between MAX, MYC, and gene regulation in SCLC.
Main Methods:
- Genome-wide analyses in genetically modified MAX-deficient SCLC cells.
- Proteomics to study protein interactions and functions.
- Analysis of gene expression profiles and transcriptional activity.
Main Results:
- MAX-deficient SCLCs exhibit ASCL1 or NEUROD1 expression patterns and lack MYC activity.
- MAX restoration induces differentiation-associated gene expression, modulated by MYC coexpression.
- MAX deficiency impairs MGA occupancy within the ncPRC1.6 complex, affecting gene repression.
Conclusions:
- MAX-mutant SCLCs are characterized by specific cell identities and are MYC-independent.
- MAX loss leads to deficient ncPRC1.6-mediated gene repression, impacting stem cell and DNA repair pathways.
- MAX restitution can restore tumor suppressor functions, offering potential therapeutic insights.
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