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Antonio Gomez



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    MA17 - Molecular Mechanisms and Therapies (ID 143)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MA17.05 - DNA-Binding and Gene Expression Profiles in Max Deficient Small Cell Lung Cancer (Now Available) (ID 377)

      15:45 - 17:15  |  Author(s): Antonio Gomez

      • Abstract
      • Presentation
      • Slides

      Background

      The MYC pathway is frequently altered in cancer, mostly by gene activation of the MYC-family of oncogenes (fMYC) but also by genetic inactivation of MAX, the obligate partner of MYC. While the oncogenic properties of fMYC have been extensively studied, the tumour suppressor role of MAX and the function of fMYC in MAX-mutant cells remain unclear. Further, inactivating mutations in MGA, a gene that codes for another MAX-binding partner, have been found in lung cancer. MGA is a component of the non-canonical polycomb repressive complex 1 (ncPRC1) but its precise role in lung cancer development is unknown.

      Method

      RNA-sequencing, chromatin immunoprecipitation and proteomic analysis were performed to identify and compare the DNA binding and gene expression profiles of MYC, MGA and MAX in MAX-restituted human small cell lung cancer (SCLC)-derived cell lines.

      Result

      SCLC is a high-grade neuroendocrine type of lung cancer with recurrent inactivating mutations in MAX. Recent findings have described two major SCLC subtypes based on the high expression of either ASCL1 or NEUROD1 transcription factors. According to this, ASCL1 and NEUROD1 control the expression of different set of genes which defines the two subgroups of SCLC. Here, we found that MAX-mutant SCLC cells belong to the ASCL1-transcription factor dependent group of SCLCs. In the absence of MAX, even after ectopic overexpression of MYC, there was no recruitment of MYC to the DNA. The DNA binding profile of MAX in MAX-restituted cells remained unaltered after co-overexpression of MYC, despite opposed effects in gene expression. Moreover, restitution of MAX significantly shifted the DNA occupancy of MGA, from E2F6 consensus binding sites to MYC-consensus binding sites (E-boxes). Our observations also demonstrated that ncPRC1 complex is formed regardless of the presence or absence of MAX.

      Conclusion

      Our data supports that MYC lacks transactivation capabilities in the absence of MAX and that the tumour suppressor role of MAX relies on its capability to counteract the gene expression triggered by its partnering with fMYC. Further, we conclude that the tumor suppressor role of MGA may be related, in part, to the regulation of E2F6 promoters.

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