The overexpression of MYC genes is frequently found in many human cancers, including adult and pediatric malignant brain tumors. Targeting MYC genes continues to be challenging due to their undruggable nature. Using our prediction algorithm, the nine-amino-acid activation domain (9aaTAD) has been identified in all four Yamanaka factors, including c-Myc. The predicted activation function was experimentally demonstrated for all these short peptides in transactivation assay. We generated a set of c-Myc constructs (1-108, 69-108 and 98-108) in the N-terminal regions and tested their ability to initiate transcription in one hybrid assay. The presence and absence of 9aaTAD (region 100-108) in the constructs strongly correlated with their activation functions (5-, 3- and 67-times respectively). Surprisingly, we observed co-activation function of the myc region 69-103, called here acetyl-TAD, previously described by Faiola et al. (Mol Cell Biol 25:10220-10234, 2005) and characterized in this study as a new domain collaborating with the 9aaTAD. We discovered strong interactions on a nanomolar scale between the Myc-9aaTAD activation domains and the KIX domain of CBP coactivator. We showed conservation of the 9aaTADs in the MYC family. In summary for the c-Myc oncogene, the acetyl-TAD and the 9aaTAD domains jointly mediated activation function. The c-Myc protein is largely intrinsically disordered and therefore difficult to target with small-molecule inhibitors. For the c-Myc driven tumors, the strong c-Myc interaction with the KIX domain represents a promising druggable target.
- MeSH
- aktivace transkripce MeSH
- lidé MeSH
- proteinové domény MeSH
- protoonkogenní proteiny c-myc * metabolismus genetika MeSH
- sekvence aminokyselin MeSH
- vazba proteinů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically. Significance: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers.
- MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prsu * metabolismus genetika patologie MeSH
- protoonkogenní proteiny c-myc * metabolismus genetika MeSH
- regulace genové exprese u nádorů MeSH
- ribonukleotidy * farmakologie MeSH
- stabilita RNA * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The transcription factor c-Myc, a key regulator of cellular processes, has long been associated with roles in cell proliferation and apoptosis. This review analyses the multiple functions of c-Myc by examining the different c-Myc isoforms in detail. The impact of different c-Myc isoforms, in particular p64 and p67, on fundamental biological processes remains controversial. It is necessary to investigate the different isoforms in the context of proto-oncogenesis. The current knowledge base suggests that neoplastic lesions may possess the means for self-destruction via increased c-Myc activity. This review presents the most relevant information on the c-Myc locus and focuses on a number of isoforms, including p64 and p67. This compilation provides a basis for the development of therapeutic approaches that target the potent growth arresting and pro-apoptotic functions of c-Myc. This information can then be used to develop targeted interventions against specific isoforms with the aim of shifting the oncogenic effects of c-Myc from pro-proliferative to pro-apoptotic. The research summarised in this review can deepen our understanding of how c-Myc activity contributes to different cellular responses, which will be crucial in developing effective therapeutic strategies; for example, isoform-specific approaches may allow for precise modulation of c-Myc function.
Mitochondria are central for cancer responses to therapy-induced stress signals. Refractory tumors often show attenuated sensitivity to apoptotic signaling, yet clinically relevant molecular actors to target mitochondria-mediated resistance remain elusive. Here, we show that MYC-driven neuroblastoma cells rely on intact mitochondrial ribosome (mitoribosome) processivity and undergo cell death following pharmacological inhibition of mitochondrial translation, regardless of their multidrug/mitochondrial resistance and stem-like phenotypes. Mechanistically, inhibiting mitoribosomes induced the mitochondrial stress-activated integrated stress response (ISR), leading to downregulation of c-MYC/N-MYC proteins prior to neuroblastoma cell death, which could be both rescued by the ISR inhibitor ISRIB. The ISR blocks global protein synthesis and shifted the c-MYC/N-MYC turnover toward proteasomal degradation. Comparing models of various neuroectodermal tumors and normal fibroblasts revealed overexpression of MYC proteins phosphorylated at the degradation-promoting site T58 as a factor that predetermines vulnerability of MYC-driven neuroblastoma to mitoribosome inhibition. Reducing N-MYC levels in a neuroblastoma model with tunable MYCN expression mitigated cell death induction upon inhibition of mitochondrial translation and functionally validated the propensity of neuroblastoma cells for MYC-dependent cell death in response to the mitochondrial ISR. Notably, neuroblastoma cells failed to develop significant resistance to the mitoribosomal inhibitor doxycycline over a long-term repeated (pulsed) selection. Collectively, we identify mitochondrial translation machinery as a novel synthetic lethality target for multidrug-resistant MYC-driven tumors.
- MeSH
- apoptóza MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- neuroblastom * farmakoterapie genetika metabolismus MeSH
- protoonkogen n-myc genetika metabolismus MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- signální transdukce MeSH
- umělé letální mutace * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream-effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34+ /CD38- leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22T315I . The BRD4-targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1-resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast-induced TKI resistance of CML LSC in a co-culture system and to block interferon-gamma-induced upregulation of the checkpoint antigen PD-L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC.
- MeSH
- bcr-abl fúzní proteiny MeSH
- blastická krize farmakoterapie MeSH
- chemorezistence MeSH
- chronická myeloidní leukemie * farmakoterapie genetika metabolismus MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- jaderné proteiny * genetika MeSH
- kmenové buňky MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proteiny buněčného cyklu MeSH
- protoonkogenní proteiny c-myc MeSH
- transkripční faktory genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase-associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition-induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including PLK1. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab in vitro, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. SIGNIFICANCE: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.
- MeSH
- antigeny CD20 MeSH
- apoptóza MeSH
- difúzní velkobuněčný B-lymfom farmakoterapie genetika metabolismus patologie MeSH
- fosforylace MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- proliferace buněk MeSH
- protinádorové látky imunologicky aktivní farmakologie MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- protoonkogenní proteiny c-pim-1 antagonisté a inhibitory MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- rituximab farmakologie MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.
- MeSH
- B-buněčný lymfom enzymologie genetika patologie MeSH
- B-lymfocyty enzymologie patologie MeSH
- DEAD-box RNA-helikasy genetika metabolismus MeSH
- dítě MeSH
- dospělí MeSH
- homeostáze proteinů MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace ztráty funkce MeSH
- myši transgenní MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny biosyntéza genetika MeSH
- předškolní dítě MeSH
- proteom MeSH
- proteosyntéza MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- regulace genové exprese enzymů MeSH
- regulace genové exprese u nádorů MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stres endoplazmatického retikula MeSH
- vedlejší histokompatibilní antigeny genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, and angiogenesis in cancers. In this review, we analyse MYC gene networks in solid cancers. We investigate the interaction of MYC with long non-coding RNAs (lncRNAs). Furthermore, we investigate the role of MYC regulatory networks in inducing changes to cellular processes, including autophagy and mitophagy. Finally, we review the interaction and mutual regulation between MYC and lncRNAs, and autophagic processes and analyse these networks as unexplored areas of targeting and manipulation for therapeutic gain in MYC-driven malignancies.
- MeSH
- autofagie * MeSH
- genové regulační sítě * MeSH
- lidé MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- RNA dlouhá nekódující genetika metabolismus MeSH
- RNA nádorová genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.
- MeSH
- adenin analogy a deriváty farmakologie MeSH
- antigeny CD40 genetika metabolismus MeSH
- chronická lymfatická leukemie farmakoterapie genetika metabolismus patologie MeSH
- dospělí MeSH
- faktor 4 asociovaný s receptory TNF genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA genetika MeSH
- míra přežití MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádorové buňky kultivované MeSH
- následné studie MeSH
- piperidiny farmakologie MeSH
- prognóza MeSH
- protoonkogenní proteiny c-bcr antagonisté a inhibitory MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
MYC was found to be involved in many germinal center derived lymphomas, and more recently in the histological transformation of indolent mature B-cell malignancies, such as follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) and mucosa-associated lymphoid tissue lymphoma (MALT) to aggressive diffuse large B-cell lymphoma (DLBCL). Pathological MYC activity gain in lymphomas is able to overcome its regulation by repressors, which leads to bypassing the affinity-based selection of B-cells. Arguably the MYC activity gain is the most constantly observed phenomenon (>70% of cases) in transformed FL/MALT/CLL (Richter's transformation) and co-occurs with specific aberrations such as the loss of p53, CDKN2A/B, or gain of BCL2/BCL6. Here we summarize recent progress in the understanding of MYC regulatory network in lymphoma B-cells and highlight its involvement in lymphomas' histological transformation by regulating cyclins, CDKs, p21, p27, BCL2, E2F, FOXP1, BCR signaling components, and non-coding microRNA (miRNA) genes such as miR-150, miR-29, miR-17-92, and miR-34a.
- MeSH
- B-lymfocyty MeSH
- chronická lymfatická leukemie * MeSH
- difúzní velkobuněčný B-lymfom * MeSH
- folikulární lymfom * MeSH
- forkhead transkripční faktory MeSH
- lidé MeSH
- lymfom z B-buněk marginální zóny * MeSH
- protoonkogenní proteiny c-myc * MeSH
- represorové proteiny MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
