MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors

Urbanski, Laura M.; Brugiolo, Mattia; Park, SungHee; Angarola, Brittany; Leclair, Nathan K.; Yurieva, Marina; Palmer, Phil; Sahu, Shivani; Anczuków, Olga

doi:10.1016/j.celrep.2022.111704

Cited by 34 publications

(25 citation statements)

References 129 publications

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“…MYC is one of the most studied oncogenes known to promote cell proliferation. Several studies have reported a significant correlation between high MYC V1 and V2 scores, worse survival, and cancer aggressiveness [ 29 , 30 , 31 , 32 ]. Strippoli et al demonstrated that higher MYC levels are associated significantly with higher and faster resistance to anti-EGFR chemotherapy treatment.…”

Section: Discussionmentioning

confidence: 99%

Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer

Kula

Dawidowicz

Mielcarska

et al. 2023

IJMS

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The study aimed to investigate correlations between HHLA2 levels and parameters, including microsatellite instability (MSI) status, CD8+ cells, and histopathological features: budding, tumor-infiltrating lymphocytes (TILs), TNM scale, grading, cytokines, chemokines, and cell signaling moleculesin colorectal cancer (CRC). Furthermore, the immune infiltration landscape and HHLA2-related pathways in colorectal cancer using available online datasets were analyzed. The study included 167 patients diagnosed with CRC. Expression of HHLA2 was detected by immunohistochemistry method (IHC) and enzyme-linked immunosorbent assay (ELISA). The IHC was used to evaluate the MSI and CD8+ status. The budding and TILs were measured using a light microscope. The concentrations of cytokines, chemokines, and cell signaling molecules were measured to analyze the data by the Bio-Plex Pro Human cytokine screening panel, 48 cytokine assay, and principal component analysis (PCA). Geneset enrichment analysis (GSEA) was conducted to identify HHLA2-related pathways. The biological function of HHLA2 was predicted by Gene Ontology (GO). Analysis of the immune infiltration landscape of HHLA2 in colorectal cancer was made by the web-based tool Camoip. High HHLA2 expression was detected in CRC tumor tissues compared to the adjacent noncancerous tissues. The percentage of HHLA2-positive tumors was 97%. GSEA and GO showed that HHLA2 upregulation correlated with cancer-related pathways and several biological functions. Tumor-infiltrating lymphocytes score correlated positively with IHC HHLA2 expression level percentage. There was a negative correlation between HHLA2, anti-tumor cytokines and pro-tumor growth factors. This study provides a valuable insight into the role of HHLA2 in CRC. We reveal the role of HHLA2 expression as well as a stimulatory and inhibitory immune checkpoint in colorectal cancer. Further research may verify the therapeutic values of the HHLA2-KIR3DL3/TMIGD2 pathway in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer

Kula

Dawidowicz

Mielcarska

et al. 2023

IJMS

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“…Regulation of splicing factors and splicing events by MYC has been previously noted 31 , 90 . A recent report shows that MYC- driven splicing factors regulate ~4000 splicing events across cancers 91 . Consistent with our findings, FOX and the MYC family of regulators control growth, proliferation, and survival of cells in multiple contexts during embryogenesis as well as cancer 92 , 93 .…”

Section: Discussionmentioning

confidence: 99%

Broad misappropriation of developmental splicing profile by cancer in multiple organs

et al. 2022

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Oncogenesis mimics key aspects of embryonic development. However, the underlying mechanisms are incompletely understood. Here, we demonstrate that the splicing events specifically active during human organogenesis, are broadly reactivated in the organ-specific tumor. Such events are associated with key oncogenic processes and predict proliferation rates in cancer cell lines as well as patient survival. Such events preferentially target nitrosylation and transmembrane-region domains, whose coordinated splicing in multiple genes respectively affect intracellular transport and N-linked glycosylation. We infer critical splicing factors potentially regulating embryonic splicing events and show that such factors are potential oncogenic drivers and are upregulated specifically in malignant cells. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of critical splicing factors in brain and liver. Our study provides a comprehensive demonstration of a splicing-mediated link between development and cancer, and suggest anti-cancer targets including splicing events, and their upstream splicing and transcriptional regulators.

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“…Other studies examining the programs of splicing regulation in cancer have also identified HRAS as a Myc dependent exon. Expression of several SR proteins is altered in response to Myc (Anczuków et al, 2012(Anczuków et al, , 2015, and it was recently reported that some SR proteins, particularly SRSF2, act to repress HRAS cassette exon splicing in Myc-active tumors (Urbanski et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…HRAS exon 5 inclusion was found to be anti-correlated with Myc activity across prostate and breast cancers (Phillips et al, 2020). Greater skipping of this exon was also seen in Myc-active tumors in a pan-cancer analysis that implicated a network of SR proteins in its regulation (Urbanski et al, 2022).…”

Section: Hras Exon 5 As Repressed By Myc Transformation Across Multip...mentioning

confidence: 94%

“…Myc-correlated exons were enriched in genes encoding splicing regulatory proteins and core spliceosomal components, as well as other cellular functions. The splicing of HRAS exon 5 was found to be particularly responsive to Myc activity, and the correlation between HRAS splicing and Myc activation is found in other tumor types (Phillips et al, 2020;Urbanski et al, 2022). HRAS belongs to the Ras oncogene family, regulates cell division, and is involved in multiple signal transduction pathways (Crespo and León, 2000;Moore et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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The RNA binding proteins hnRNP H and F regulate splicing of a MYC dependent HRAS exon in Prostate Cancer Cells

Chen

Yang

Zhang

et al. 2022

Preprint

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The Myc proto-oncogene contributes to the pathogenesis of more than half of human cancers. Malignant transformation by Myc transcriptionally upregulates the core pre-mRNA splicing machinery and causes mis-regulation of alternative splicing. However, our understanding of how splicing changes are directed by Myc is limited. We performed a signaling pathway-guided splicing analysis to identify Myc dependent splicing events. These included an HRAS cassette exon repressed by Myc across multiple tumor types. To molecularly dissect the regulation of this HRAS exon, we used antisense oligonucleotide tiling to identify splicing enhancers and silencers in its flanking introns. RNA binding motif prediction indicated multiple binding sites for hnRNP H and hnRNP F within these cis-regulatory elements. Using siRNA knockdown and cDNA expression, we found that both hnRNP H and F activate the HRAS cassette exon.Mutagenesis and targeted RNA immunoprecipitation implicate two downstream G-rich elements in this splicing activation. Analyses of ENCODE RNA-seq datasets confirmed hnRNP H regulation of HRAS splicing. Analyses of RNA-seq datasets across multiple cancers showed a negative correlation of hnRNP H gene expression with Myc hallmark enrichment, consistent with the effect of hnRNP H on HRAS splicing. Interestingly, hnRNP F expression showed a positive correlation with Myc hallmarks and thus was not consistent with the observed effects of hnRNP F. Loss of hnRNP H/F altered cell cycle progression and induced apoptosis in the PC3 prostate cancer cell line. Collectively, our results reveal new mechanisms for Myc-dependent regulation of splicing, and point to new possible therapeutic targets in prostate cancers.SIGNIFICANCE STATMENTMyc Transformation by the proto-oncogene c-Myc causes dysregulation of the pre-mRNA splicing reaction in cancer, but it is not known how mRNA isoform changes are directed by Myc. Here, we use bioinformatics to identify a splicing event in another proto-oncogene, HRAS, that is regulated by Myc across multiple tumor types. We identify new splicing regulators, hnRNP’s H and F, that control this HRAS exon by binding to enhancer elements within its downstream intron. Additional pan-cancer bioinformatic analyses show hnRNP H expression to be anti- correlated with Myc hallmarks, consistent with the reduced splicing of the HRAS exon in Myc driven cancer. These findings uncover new mechanisms by which Myc can alter splicing in cancer cells and provide new molecular targets for potential therapeutics.

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MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors

Cited by 34 publications

References 129 publications

Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer

Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer

Broad misappropriation of developmental splicing profile by cancer in multiple organs

The RNA binding proteins hnRNP H and F regulate splicing of a MYC dependent HRAS exon in Prostate Cancer Cells

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