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Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe

ABSTRACT: MYC overexpression is a well-established cancer vulnerability, yet direct therapeutic targeting of Myc remains a challenge. Here, we identify DL78 as a potent antimitotic agent with selective anticancer activity through its regulation of Myc. DL78 demonstrated broad efficacy by inhibiting growth across nine cancer types and significantly reducing tumor burden in an in vivo model of platinum-resistant high-grade serous ovarian cancer, with no overt toxicity. DL78 preferentially targets chromosomally unstable, MYC-overexpressing cancer cells, a hallmark of high-grade serous ovarian cancer. Mechanistically, DL78 exploits Myc’s role in mitotic entry by disrupting its interaction with α-tubulin, leading to sustained mitotic arrest, mitotic catastrophe, and apoptosis while sparing nonmalignant cells. This study establishes a novel paradigm for Myc-targeted therapy by introducing DL78, which induces cancer-selective mitotic catastrophe by disrupting Myc’s interaction with α-tubulin rather than its transcriptional activity

ORGANISM(S): Homo sapiens

PROVIDER: GSE267208 | GEO | 2025/09/08

REPOSITORIES: GEO

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Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe

Project description:Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe

| PRJNA1110243 | ENA

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Project description:Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. However, previous GEMMs of high-grade serous ovarian cancer (HGSOC) have had to utilize genetics rarely or never found in human HGSOC to yield ovarian cancer within the lifespan of a mouse. MYC, an oncogene, is amongst the most amplified genes in HGSOC, but it has not previously been utilized to drive HGSOC GEMMs. We coupled Myc and dominant negative mutant p53-R270H with a fallopian tube epithelium-specific promoter Ovgp1 to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 15.1 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium (FTE). Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate the Myc and Trp53-R270H transgene was able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology directed repair mutations. Histological and transcriptomic findings are consistent with the hypothesis that serous uterine cancer may originate from the fallopian tube epithelium.

2024-01-23 | GSE238158 | GEO

ChIP-Seq of MYC in MCF-7 cells treated with AM (Actinomycin D and MG132) or DMSO.

Project description:MYC has been known to bind to thousands of promoters and exert an amplification effect on expression of most genes. Meanwhile, MYC drives tumorigenesis through the regulation of a unique set of cancer-specific targets that differ from its targets in normal cells. However, the mechanism underlying this discrepancy in MYC’s regulation in tumor and normal cells has not been fully elucidated. In this study, we discovered that MYC protein has a broad RNA binding spectrum including promoter-associated RNAs (paRNAs) and enhancer RNAs (eRNAs). MYC’s RNA binding peaks colocalize with its DNA binding sites, but not dependent on its HLHLZ domain or transcription activation domain. By further integrating multiple dimensional data from cancer cells and tumors samples, we have shown that the MYC-bound paRNAs and eRNAs can shape MYC chromatin interaction to regulate gene transcription. Finally, we have mechanistically characterized a MYC-bound eRNA, MERG1, that plays essential roles in the ERα+ breast cancer tumorigenesis. Mechanistically, MERG1 interacts with MYC and enhances MYC’s binding to the enhancer and promoter of GREB1 gene. This process specifically amplifies the target gene GREB1 expression and accelerates tumor progression. Our study demonstrates that MYC’s interaction with paRNAs and eRNAs contribute to its specific amplification of gene expression in tumorigenesis.

2025-04-30 | GSE200163 | GEO

Myc/Max dependent long antisense noncoding RNA, EVA1A-AS, participates in survival of hepatocellular carcinoma (HCC) by suppressing anti proliferating gene Eva1A.

Project description:Cancer cells associated with multiple survival strategies, and how cancer cells escape cell death under different conditions are still largely unknown. The Myc gene has been implicated in the pathogenesis of most types of human tumors. We show here that Eva1 (eva-1homolog A)/TMEM166 (transmembrane protein 166)/family with sequence similarity 176 (FAM176A) is upregulated by Myc/Max, however, overexpression of Eva1A induced mitotic catastrophe in hepatocellular carcinoma (HCC). Here, expression of Eva1A in HCC is suppressed by antisense long noncoding RNA, Eva1A-AS, that is induced also by Myc/Max, suggesting that Eva1A-AS expression supports HCC survival. Eva1A-AS is located within intron of Eva1A gene suppressed Eva1 expression by forming double stranded RNA with DiGeorge syndrome chromosomal region 8 (DGCR8). Depletion of Eva1A-AS in HepG2 cells upregulates Eva1A expression, and induced accumulation of lipid droplets and stopped cell proliferation. Furthermore, suppressed Eva1A expression levels are negatively correlated with differentiation grade in 371 primary HCCs. These data also suggest that EVA1A-AS may be useful target for a subset of HCCs.

2019-12-10 | GSE115139 | GEO

The polyamine-hypusine circuit controls an oncogenic translational program necessary for MYC-driven lymphomagenesis

Project description:MYC oncogenes are activated in broad spectrum of human malignancies and transcriptionally reprogram the genome to drive cancer cell growth. Given this it is unclear if targeting a single effector will have a therapeutic benefit. MYC activates the polyaminehypusine circuit, which post-translationally modifies the translation factor eIF5A. The hypusine axis has been proposed to suppress tumorigenesis. Here we report essential roles for hypusinated eIF5A in the development and maintenance of Myc-driven lymphoma, where loss of eIF5A hypusination abolishes malignant transformation. Mechanistically, integrating RNA-seq, Ribo-seq and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including key regulators of G1 to S phase cell cycle progression. Notably, this circuit controls Myc’s proliferative response at several levels, and it is activated across multiple tumor types. These findings suggest the hypusine circuit as a therapeutic target for a broad spectrum of malignancies.

2024-01-26 | PXD031361 | Pride

Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13

Project description:High-grade serous ovarian cancer is characterized by extensive copy number alterations, among which the amplification of MYC oncogene occurs in nearly half of tumors. We demonstrate that ovarian cancer cells highly depend on MYC for maintaining their oncogenic growth, indicating MYC as a therapeutic target for this difficult-to-treat malignancy. However, targeting MYC directly has proven difficult. We screen small molecules targeting transcriptional and epigenetic regulation, and find that THZ1 –a chemical inhibiting CDK7, CDK12, and CDK13–markedly downregulates MYC. Notably, abolishing MYC expression cannot be achieved by targeting CDK7 alone, but require the combined inhibition of CDK7, CDK12, and CDK13. In all 11 independent patient derived xenografts models derived from heavily pre-treated ovarian cancer patients, administration of THZ1 induces significant tumor growth inhibition with concurrent abrogation of MYC expression. Our study indicates that targeting these transcriptional CDKs with agents such as THZ1 may be an effective approach for MYC-dependent ovarian malignancies.

2018-06-27 | GSE116282 | GEO

FOXR2 Interacts with MYC to Promote Its Transcriptional Activities and Tumorigenesis

Project description:Combining the results of a large scale proteomic analysis of human transcription factor interaction network with knowledge databases, we identified FOXR2 as one of the top-ranked candidate proto-oncogenes. Here, we show that FOXR2 forms a stable complex with MYC and MAX and subsequently regulates cell proliferation by promoting MYC’s transcriptional activities. We demonstrated that FOXR2 is highly expressed in several breast, lung, and liver cancer cell lines and related patient tumor samples, while reduction of FOXR2 expression in a xenograft model inhibits tumor growth. These results indicate that FOXR2 acts with MYC to promote cancer cell proliferation, which is a potential tumor-specific target for therapeutic intervention against MYC-driven cancers.

2017-02-17 | GSE81381 | GEO

snoRNAs are a novel class of biologically relevant Myc targets

Project description:Myc proteins are essential regulators of animal growth during normal development, and their deregulation is one of the main driving factors of human malignancies. They function as transcription factors that (in vertebrates) control many growth- and proliferation-associated genes, and in some contexts contribute to global gene regulation. We combine ChIPseq and RNAseq approaches in Drosophila tissue culture cells to identify a core set of less than 500 Myc target genes, whose salient function resides in the control of ribosome biogenesis. Amongst these genes we find the non-coding snoRNA genes as a large novel class of Myc targets. All assayed snoRNAs are affected by Myc, and many of them are subject to direct transcriptional activation by Myc, both in Drosophila and in vertebrates. The loss of snoRNAs impairs growth during normal development, whereas their overexpression increases tumor mass in a model for neuronal tumors. This work shows that Myc acts as a master regulator of snoRNP biogenesis. In addition, in combination with recent observations of snoRNA involvement in human cancer, it raises the possibility that Myc’s transforming effects are partially mediated by this class of non-coding transcripts.

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MYC and HSF1 Cooperate to Drive PLK1 inhibitor Sensitivity in High Grade Serous Ovarian Cancer

Project description:MYC and HSF1 Cooperate to Drive PLK1 inhibitor Sensitivity in High Grade Serous Ovarian Cancer

| PRJNA1130486 | ENA

RNA-Seq of U2OS-MYC-KO-MYC-Tet-On cells with exogenous wild-type and mutant MYC expression

Project description:Transcription factor (TF) MYC binds to thousands of gene regulatory elements in the genome such as promoters and enhancers and exerts an amplification effect on the expression of most genes, regardless of the E-box motif existence. In this study, we discovered that MYC is an RNA-binding protein with a high affinity to guanosine-rich RNAs. RNAs that bind to MYC increase MYC’s chromatin occupancy, which helps with MYC-mediated regulation of gene expression. Mechanistically, two highly conserved sequences, amino acids 355-357 and 364-367, in the basic region of MYC are essential for RNA binding. Notably, alanine substitution of Lys355, Arg356, and Arg357 of MYC abolishes its RNA binding function but does not influence its complex formation ability, and E-box binding capacity of MYC:MAX dimer in vitro. However, loss of RNA binding function alone decreases MYC recruitment at gene regulatory elements in vivo, followed by a decreased MYC:MAX chromatin binding at these regions. This process further attenuates MYC-mediated gene expression. Therefore, RNA-binding-deficient MYC is compromised in promoting cancer cell proliferation. By demonstrating the mechanism of MYC-RNA interaction and the fundamental role of RNA binding activity in MYC-centric functions, our study reveals a new paradigm to MYC function and highlights an essential and probably general role of RNA binding capacity of TFs for their gene regulatory function.

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