First name
Nina
Last name
Tanaskovic
Academic Year
Year of Study
Research Center
Thesis Title
Tumor suppressor activity of the Polycomb Group Ring Finger protein Pcgf6 in Myc-induced lymphomagenesis
Thesis Abstract
The Myc oncoprotein is a bHLH-LZ transcription factor that heterodimerizes with another bHLH-LZ protein, Max, in order to bind DNA and activate transcription. Max can also di- merize with a variety of alternative bHLH-LZ partners, including Mxd1-4, Mnt and Mga, that act as transcriptional repressors, and are thought to counteract Myc activity at common target genes. Max and Mga are also part of the variant Polycomb Repressive Complex PRC1.6, suggesting that their antagonistic effect on Myc activity may be mediated through PRC1.6. The role of Max has been extensively studied in neuroendocrine carcinomas, spe- cifically in Pheocromocytoma (PC) and Small Cell Lung Cancer (SCLC), where loss of Max can lead to tumor suppression. Beside loss of Max, Myc amplification or loss of Mga can also occur in SCLC: all of these events are mutually exclusive, pointing to a common functional consequence. In light of these observations, we hypothesized that Mga/Max may recruit the PRC1.6 complex which can then antagonize Myc/Max function at a common set of target genes. We further speculated that this may endow Mga and/or Pcgf6 with a general tumor suppressor activity, possibly extending to tumor types other than PC or SCLC.
With this project, we dissected a specific molecular mechanism of Eμ-myc lymphomagene- sis. Specifically, we unraveled a novel role of Pcgf6 as tumor suppressor in Myc-induced lymphoma development. B-cell specific Pcgf6 deletion leads to accelerated tumor for- mation, while, on the other hand, such deletion of Mga does not cause similar phenotype.
Mga and Pcgf6 are part of the same repressive complex (PRC1.6) and the presence of Mga is essential for Pcgf6 chromatin association. Considering this, our data strongly imply that in B-cell lymphomagenesis, Pcgf6 exerts its tumor suppressive function in PRC1.6- and Mga- independent manner.
Chromatin distribution of Myc, Max and Pcgf6 in Eμ-myc lymphomas suggest that Pcgf6 does not affect the association of Myc and Max with chromatin. Therefore, with these anal- yses we demonstrate that PRC1.6, as assessed by Pcgf6 distribution, does not limit Myc association with chromatin, but rather bind to common set of target genes.
Moreover, with transcriptomic profiling of Eμ-myc lymphomas, we showed that tumor sup- pressive role of Pcgf6 is conducted via non-transcriptional mechanism. Mild changes ob- served in tumors scored down regulation of genes involved in immune surveillance path- ways, which opened the door towards an alternative tumor suppressive role of Pcgf6, exe- cuted through immune surveillance mechanisms. Dissecting different populations of tumor- infiltrated cells in our Pcgf6 KO Eμ-myc tumors, we preliminary showed that the loss of Pcgf6 leads to a global downregulation of infiltrated T-cells, specifically effector CD8+ and CD4+, suggesting its non-cell autonomous function and its involvement in T-cell recruitment and/or activation.
In light of these data, we propose a novel mechanism of Pcgf6-mediated tumor suppression that is conducted in non-transcriptional PRC1.6-independent manner and most likely through immune surveillance pathways.
With this project, we dissected a specific molecular mechanism of Eμ-myc lymphomagene- sis. Specifically, we unraveled a novel role of Pcgf6 as tumor suppressor in Myc-induced lymphoma development. B-cell specific Pcgf6 deletion leads to accelerated tumor for- mation, while, on the other hand, such deletion of Mga does not cause similar phenotype.
Mga and Pcgf6 are part of the same repressive complex (PRC1.6) and the presence of Mga is essential for Pcgf6 chromatin association. Considering this, our data strongly imply that in B-cell lymphomagenesis, Pcgf6 exerts its tumor suppressive function in PRC1.6- and Mga- independent manner.
Chromatin distribution of Myc, Max and Pcgf6 in Eμ-myc lymphomas suggest that Pcgf6 does not affect the association of Myc and Max with chromatin. Therefore, with these anal- yses we demonstrate that PRC1.6, as assessed by Pcgf6 distribution, does not limit Myc association with chromatin, but rather bind to common set of target genes.
Moreover, with transcriptomic profiling of Eμ-myc lymphomas, we showed that tumor sup- pressive role of Pcgf6 is conducted via non-transcriptional mechanism. Mild changes ob- served in tumors scored down regulation of genes involved in immune surveillance path- ways, which opened the door towards an alternative tumor suppressive role of Pcgf6, exe- cuted through immune surveillance mechanisms. Dissecting different populations of tumor- infiltrated cells in our Pcgf6 KO Eμ-myc tumors, we preliminary showed that the loss of Pcgf6 leads to a global downregulation of infiltrated T-cells, specifically effector CD8+ and CD4+, suggesting its non-cell autonomous function and its involvement in T-cell recruitment and/or activation.
In light of these data, we propose a novel mechanism of Pcgf6-mediated tumor suppression that is conducted in non-transcriptional PRC1.6-independent manner and most likely through immune surveillance pathways.
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