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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.

2021-09-22 | PXD017658 | Pride

Pcgf6 suppresses Myc-induced lymphomagenesis [RNA-seq]

Project description:Max is an obligate dimerization partner for the Myc transcription factors and for several repressors, such as Mnt, Mxd1-4 and Mga, collectively thought to antagonize Myc function in transcription and oncogenesis. Mga, in particular, is part of the variant Polycomb group repressive complex PRC1.6. Here, we show that ablation of the distinct PRC1.6 subunit Pcgf6 – but not Mga – accelerates Myc-induced lymphomagenesis in Eµ-myc transgenic mice. Unexpectedly, however, Pcgf6 loss shows no significant impact on transcriptional profiles, in neither pre-tumoral B-cells, nor lymphomas. Altogether, these data unravel an unforeseen, Mga- and PRC1.6-independent tumor suppressor activity of Pcgf6.

2021-12-05 | GSE189999 | GEO

Pcgf6 suppresses Myc-induced lymphomagenesis [ChIP-seq]

2021-12-05 | GSE189989 | GEO

CUT&RUN studies comparing occupancy of MAX, MGA, MYC and L3MBTL2 occupancy in Empty vector and sgMGA transduced A549 lung adenocarcinoma cells

Project description:The goal of this study was to examine the genomic occupancy of MAX, MGA, MYC and L3MBTL2 in MGA depleted vs. control cells

2020-11-16 | GSE161539 | GEO

Ablation of Max expression induces meiotic onset in sexually undifferentiated germ cells

Project description:MAX (MYC Associated Factor X) is generally known as a mandatory partner for MYC transcription factor, which activates various genes involved in cell growth and metabolism. On the other hand, MAX, when interacting with MGA, forms the polycomb repressive complex (PRC) 1.6, one of the subtypes of PRC1, which directs the transcriptionally repressed chromatin state. Although physiological significance is not known at present, we have previously demonstrated that mouse embryonic stem cells (ESCs) bear a potential to onset meiosis, albeit not germ cells, and PRC1.6 prevent ESCs from their ectopic onset of meiosis (Suzuki et al., 2016, Nat. Commun. 7:11056 doi: 10.1038/ncomms11056). In this study, we aimed to investigate the role of Max in germ cells in vivo by performing the primordial germ cell-specific knockout of the Max gene.

2024-03-13 | GSE233556 | GEO

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

| PRJNA608275 | ENA

CUT&RUN comparing occupancy of MAX, MNT, MYC in MAX WT and KO B220+ cells

Project description:The goal of this study was to genomic occupancy of MAX, MNT, MYC and E2F1 in B cells in the presence and absence of transcription factor MAX Although MAX is regarded as an obligate dimerization partner for MYC, its function in normal development and neoplasia is poorly defined. We show that B-cell specific deletion of Max has a modest effect on B-cell development but completely abrogates E -Myc driven lymphomagenesis. While Max loss only affects a few hundred genes in normal B cells, it leads to the global downregulation of Myc-activated genes in premalignant E -Myc cells. We show that the balance between MYC-MAX and MNT-MAX interactions in B cells shifts in pre-malignant B cells towards a MYC driven transcriptional program. Moreover, we find that MAX loss leads to a significant reduction in MYC protein levels and downregulation of direct transcriptional targets, including regulators of MYC stability. This phenomenon is also observed in multiple cell lines treated with MYC-MAX dimerization inhibitors. Our work uncovers a layer of Myc autoregulation critical for lymphomagenesis yet partly dispensable for normal development.

2019-06-20 | GSE132967 | GEO

Functional interplay between c-Myc and Max in B lymphocyte differentiation

Project description:The Myc proteins (N-, L- and c-Myc) are transcription factors involved in many biological functions such as regulation of cell proliferation, differentiation, metabolism and apoptosis. A large number of human cancers show enhanced expression of myc family proto-oncogenes as one of their hallmarks. These proteins contain a basic region/helix-loop-helix/leucine zipper (bHLHZip) domain that mediates DNA binding and heterodimerization with its partner Max (Myc/Max heterodimer). Among Myc proteins, c-Myc is the most widely expressed and relevant in primary B lymphocytes. Some reports have implied that c-Myc can perform some functions without Max in different cell contexts. However, the functional interplay in vivo between c-Myc and Max during B lymphocyte differentiation is not well-known. Here we show that c-Myc requires Max. However, key biological processes such as cell differentiation and DNA replication can initially progress without c-Myc/Max heterodimer in primary B lymphocytes. We found that B lymphocytes lacking Myc, Max or both showed upregulation of signalling pathways associated with the B cell receptor. Our data suggest that c-Myc/Max heterodimers are not essential for the initiation of certain biological processes in B lymphocytes. Rather, c-Myc/Max are necessary for fine-tuning the initial response in these cells after activation.

2018-08-20 | GSE115915 | GEO

CUT&RUN comparing the occupancy of MAX, MNT, MGA, MYC and RNA pol II Ser5 in a MAX null vs MAX reconstituted mouse SCLC line (mRPMaxKO)

Project description:The goal of this study was to compare the genomic occupancy of MAX, MNT, MGA and RNA pol II Ser5 in MAX restored versus MAX null SCLC (mRPMaxKO)

2020-06-06 | GSE146388 | GEO

Sirt1, p53 and p38MAPK are crucial regulators of detrimental phenotypes of ESCs with Max expression ablation

Project description:Ablation of expression of the Max gene encoding a Myc protein partner in ES cells provoked two major phenomena, i.e. loss of pluripotency and apoptotic cell death. We found that nicotinamide (Nam) significantly alleviates these Max expression ablation-coupled phenotypes in ES cells. To see the alleviation effect of Nam on the overall expression profile of Max-null ES cells whose Max expression is controlled by the tet-off system, we eliminated Max expression by adding doxycycline (Dox) in the presence of Nam.

2012-08-28 | GSE37917 | GEO

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