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c-Myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression in mice with only mild and fully reversible side effects, suggesting this to be a viable therapeutic strategy. Here we reassess the challenges of directly targeting c-Myc, evaluate lessons learned from current inhibitors, and explore how future strategies such as miniaturisation of Omomyc and targeting E-box binding could facilitate translation of c-Myc inhibitors into the clinic.

Purpose Long noncoding RNAs (lncRNAs) have been shown to have functional roles in cancer biology and are deregulated in many tumors. The specific aim of this study was to determine the role of a long noncoding RNA CCAT1 in the progression of gastric carcinoma and discover which factors contribute to the deregulation of CCAT1. Methods A computational screen of CCAT1 promoter was conducted to search for transcription-factor-binding sites. The association of c-Myc with the CCAT1 promoter in vivo was tested by chromatin immunoprecipitation assay. CCAT1 promoter activities were examined by luciferase reporter assay. The function of the c-Myc binding site in the CCAT1 promoter region was tested by a promoter assay with nucleotide substitutions in the putative E-box. The effect of CCAT1 on gastric carcinoma cell proliferation and migration was tested using in vitro cell proliferation and migration assays. Results CCAT1 levels were markedly increased in gastric carcinoma tissues compared with normal tissues. c-Myc directly binds to the E-box element in the promoter region of CCAT1 , and when ectopically expressed increased promoter activity and expression of CCAT1. Nucleotide substitutions in the E-box element in the promoter region abrogated c-Myc-dependent promoter activation. The expression of CCAT1 and c-Myc shows strong association in gastric carcinomas. Moreover, abnormally expressed CCAT1 promotes cell proliferation and migration. Conclusions These data suggest that c-Myc induction of CCAT1 holds an important role in gastric carcinoma and implicate the potential application of CCAT1 in the treatment of gastric carcinoma.

Targeting “undruggable” targets with intrinsically disordered structures is of great significance for the treatment of disease. The transcription factor c‐Myc controls global gene expression and is an attractive therapeutic target for multiple types of cancers. However, due to the lack of defined ligand binding pockets, targeted c‐Myc have thus far been unsuccessful. Herein, to address the dilemma of lacking ligands, an efficient and high throughput aptamer screening strategy is established, named polystyrene microwell plate‐based systematic evolution of ligands by exponential enrichment (microwell‐SELEX), and identify the specific aptamer (MA9C1) against c‐Myc. The multifunctional aptamer‐based Proteolysis Targeting Chimeras (PROTAC) for proteolysis of the c‐Myc (ProMyc) is developed using the aptamer MA9C1 as the ligand. ProMyc not only significantly degrades c‐Myc by the ubiquitin‐proteasome system, but also reduces the Max protein, synergistically inhibiting c‐Myc transcriptional activity. Combination of the artificial cyclization and anti‐PD‐L1 aptamer (PA1)‐based delivery system, circular PA1‐ProMyc chimeras achieve tumor regression in the xenograft tumor model, laying a solid foundation for the development of efficacious c‐Myc degrader for the clinic. Therefore, this aptamer‐based degrader provides an invaluable potential degrader in drug discovery and anti‐tumor therapy, offering a promising degrader to overcome the challenge of targeting intractable targets. The drugs against “Undruggable” targets remain an enormous challenge in drug discovery. Aptamers are used to address the ligand deficiency and isolate the anti‐c‐Myc aptamer. The aptamer‐based PROTAC that efficiently degrades c‐Myc (ProMyc) is developed. Based on the aptamer (PA1) delivery system, circular PA1‐ProMyc displays powerful antitumor activity in the tumor model, offering a potential degrader for intractable targets.

Metastatic, drug-resistant ovarian cancer is the deadliest form of gynecological cancer afflicting women globally, with > 49% relapse rate following initial diagnosis, surgery and treatment. High-grade serous ovarian cancer is the most diagnosed type of ovarian cancer. In the USA, 21,000 patients are diagnosed annually, with > 50% of patients succumbing to the disease due to metastasis and treatment resistance. The mainstay treatment for ovarian cancer is platinum-based chemotherapy, such as cisplatin or carboplatin and in combination with a taxane (paclitaxel/docetaxel). However, patients often become resistant to it, due to the pervasive oncogenic signal driving cancer drug resistance. One such oncogene is c-MYC. 30–60% of high-grade serous and drug-resistant (paclitaxel and carboplatin) ovarian cancer overexpress c-MYC, leading to progressive disease and mortality. Herein, it was shown that the novel c-MYC mRNA drug 3’UTRMYC1-18 achieved a dose-dependent titratable downregulation of the c-MYC mRNA with a half-maximal inhibitory concentration superior to the standard-of-care drugs, and with anti-cancer migration and viability properties. By using patient-derived xenograft (PDX) in-vivo, it was shown that the c-MYC mRNA drug significantly inhibited ovarian cancer through the downregulation of c-MYC, programmed death-ligand 1, paired box gene 8 and p21. This drug provides a novel therapy to target drug-resistant ovarian cancer cells. Graphical Abstract Aggressive metastatic ovarian cancer cells with c-MYC, PD-L1, PAX8 and p21 upregulation were treated with 3’UTRMYC1-18. The destabilized 3’UTRMYC1-18 recognizes multiple exons on the target c-MYC mRNA. During translation, the ribosome stalls in-frame on the destabilized c-MYC mRNA, which triggers the EXOSC4-PELO and RNA exosome complex to degrade the c-MYC transcript, leading to the downregulation of the c-MYC-PD-L1-PAX8-p21 complex and, in turn, to the inhibition of the ovarian cancer cells. PD-L1, programmed death-ligand 1; PAX8, paired box gene 8; EXOSC4, exosome component 4; PELO, Pelota MRNA surveillance and ribosome rescue factor.

Overexpression of MYC oncogene is highly prevalent in many malignancies such as aggressive triple-negative breast cancers (TNBCs) and it is associated with very poor outcome. Despite decades of research, attempts to effectively inhibit MYC, particularly with small molecules, still remain challenging due to the featureless nature of its protein structure. Herein, we describe the engineering of the dominant-negative MYC peptide (OmoMYC) linked to a functional penetrating ‘Phylomer’ peptide (FPPa) as a therapeutic strategy to inhibit MYC in TNBC. We found FPPa-OmoMYC to be a potent inducer of apoptosis (with IC 50 from 1–2 µM) in TNBC cells with negligible effects in non-tumorigenic cells. Transcriptome analysis of FPPa-OmoMYC-treated cells indicated that the fusion protein inhibited MYC-dependent networks, inducing dynamic changes in transcriptional, metabolic, and apoptotic processes. We demonstrated the efficacy of FPPa-OmoMYC in inhibiting breast cancer growth when injected orthotopically in TNBC allografts. Lastly, we identified strong pharmacological synergisms between FPPa-OmoMYC and chemotherapeutic agents. This study highlights a novel therapeutic approach to target highly aggressive and chemoresistant MYC-activated cancers.

MYC genes have both essential roles during normal development and exert oncogenic functions during tumorigenesis. Expression of a dominant-negative allele of MYC, termed OmoMYC, can induce rapid tumor regression in mouse models with little toxicity for normal tissues. How OmoMYC discriminates between physiological and oncogenic functions of MYC is unclear. We have solved the crystal structure of OmoMYC and show that it forms a stable homodimer and as such recognizes DNA in the same manner as the MYC/MAX heterodimer. OmoMYC attenuates both MYC-dependent activation and repression by competing with MYC/MAX for binding to chromatin, effectively lowering MYC/MAX occupancy at its cognate binding sites. OmoMYC causes the largest decreases in promoter occupancy and changes in expression on genes that are invaded by oncogenic MYC levels. A signature of OmoMYC-regulated genes defines subgroups with high MYC levels in multiple tumor entities and identifies novel targets for the eradication of MYC-driven tumors.

Long noncoding RNAs (lncRNAs) function through a diverse array of mechanisms that are not presently fully understood. Here, we sought to find lncRNAs differentially regulated in cancer cells resistant to either TNF-related apoptosis-inducing ligand (TRAIL) or the Mcl-1 inhibitor UMI-77, agents that act through the extrinsic and intrinsic apoptotic pathways, respectively. This work identified a commonly up-regulated lncRNA, ovarian adenocarcinoma-amplified lncRNA (OVAAL), that conferred apoptotic resistance in multiple cancer types. Analysis of clinical samples revealed OVAAL expression was significantly increased in colorectal cancers and melanoma in comparison to the corresponding normal tissues. Functional investigations showed that OVAAL depletion significantly inhibited cancer cell proliferation and retarded tumor xenograft growth. Mechanically, OVAAL physically interacted with serine/threonine-protein kinase 3 (STK3),which, in turn, enhanced the binding between STK3 and Raf-1. The ternary complex OVAAL/STK3/Raf-1 enhanced the activation of the RAF protooncogene serine/threonine-protein kinase (RAF)/mitogen-activated protein kinase kinase 1 (MEK)/ERK signaling cascade, thus promoting c-Myc–mediated cell proliferation and Mcl-1–mediated cell survival. On the other hand, depletion of OVAAL triggered cellular senescence through polypyrimidine tract-binding protein 1 (PTBP1)–mediated p27 expression, which was regulated by competitive binding between OVAAL and p27 mRNA to PTBP1. Additionally, c-Myc was demonstrated to drive OVAAL transcription, indicating a positive feedback loop between c-Myc and OVAAL in controlling tumor growth. Taken together, these results reveal that OVAAL contributes to the survival of cancer cells through dual mechanisms controlling RAF/MEK/ERK signaling and p27-mediated cell senescence.

Background Long non-coding RNAs (lncRNAs) have been associated with non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms of their specific roles in mediating aerobic glycolysis have been poorly explored. Methods Next-generation RNA sequencing assay was performed to identify the differentially expressed RNAs between NSCLC tissues with high 18 F-fluorodeoxyglucose (FDG) uptake and their adjacent normal lung tissues. LINC01123 expression in NSCLC tissues was measured by real-time PCR and in situ hybridization (ISH) assay. The biological role of LINC01123 in cell growth and aerobic glycolysis capability was determined by performing functional experiments in vitro and in vivo. Further, the transcription of LINC01123 was explored by bioinformatics analysis, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay. RNA immunoprecipitation (RIP) and luciferase analyses were used to confirm the predicted competitive endogenous RNA (ceRNA) mechanisms between LINC01123 and c-Myc. Results Three hundred sixty-four differentially expressed genes were identified in RNA-seq assay, and LINC01123 was one of the most overexpressed lncRNAs. Further validation in expanded NSCLC cohorts confirmed that LINC01123 was upregulated in 92 paired NSCLC tissues and associated with poor survival. Functional assays showed that LINC01123 promoted NSCLC cell proliferation and aerobic glycolysis. Mechanistic investigations revealed that LINC01123 was a direct transcriptional target of c-Myc. Meanwhile, LINC01123 increased c-Myc mRNA expression by sponging miR-199a-5p. In addition, rescue experiments showed that LINC01123 functioned as an oncogene depending on miR-199a-5p and c-Myc. Conclusion Since LINC01123 is upregulated in NSCLC, correlates with prognosis, and controls proliferation and aerobic glycolysis by a positive feedback loop with c-Myc, it is expected to be a potential biomarker and therapeutic target for NSCLC.

Deregulated expression of c-Myc is an important molecular hallmark of cancer. The oncogenic function of c-Myc has been largely attributed to its intrinsic nature as a master transcription factor. Here, we report the long noncoding RNA (lncRNA) E2F1 messenger RNA (mRNA) stabilizing factor (EMS) as a direct c-Myc transcriptional target. EMS functions as an oncogenic molecule by promoting G1/S cell cycle progression. Mechanistically, EMS cooperates with the RNA binding protein RALY to stabilize E2F1 mRNA, and thereby increases E2F1 expression. Furthermore, EMS is able to connect c-Myc to cell cycle control and tumorigenesis via modulating E2F1 mRNA stability. Together, these findings reveal a previously unappreciated mechanism throughwhich c-Myc induces E2F1 expression and also implicate EMS as an important player in the regulation of c-Myc function.

The limited efficacy of the current antitumor microenvironment strategies is due in part to the poor understanding of the roles and relative contributions of the various tumor stromal cells to tumor development. Here, we describe a versatile in vivo anthrax toxin protein delivery system allowing for the unambiguous genetic evaluation of individual tumor stromal elements in cancer. Our reengineered tumor-selective anthrax toxin exhibits potent antiproliferative activity by disrupting ERK signaling in sensitive cells. Since this activity requires the surface expression of the capillary morphogenesis protein-2 (CMG2) toxin receptor, genetic manipulation of CMG2 expression using our cell-type–specific CMG2 transgenic mice allows us to specifically define the role of individual tumor stromal cell types in tumor development. Here, we established mice with CMG2 only expressed in tumor endothelial cells (ECs) and determined the specific contribution of tumor stromal ECs to the toxin’s antitumor activity. Our results demonstrate that disruption of ERK signaling only within tumor ECs is sufficient to halt tumor growth. We discovered that c-Myc is a downstream effector of ERK signaling and that the MEK–ERK–c-Myc central metabolic axis in tumor ECs is essential for tumor progression. As such, disruption of ERK–c-Myc signaling in host-derived tumor ECs by our tumor-selective anthrax toxins explains their high efficacy in solid tumor therapy.