Myc deletion rescues Apc deficiency in the small intestine

Sansom, Owen J.; Méniel, Valérie S.; Muncan, Vanesa; Phesse, Toby J.; Wilkins, Julie; Reed, Karen Ruth; Vass, Keith; Athineos, Dimitris; Clevers, Hans; Clarke, Alan R.

doi:10.1038/nature05674

Cited by 535 publications

(556 citation statements)

References 23 publications

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“…c-MYC has attracted particular attention, since it is universally deregulated in colorectal tumors, and since its function in these tumors is essential and nonredundant (15). Cancer treatments targeting c-MYC would thus severely restrict the potential for drug resistance.…”

Section: Discussionmentioning

confidence: 99%

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The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Diefenbacher¹,

Popov

Blake³

et al. 2014

J. Clin. Invest.

127

141

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R e s e a R c h a R t i c l e3 4 0 7 jci.org Volume 124 Number 8 August 2014 IntroductionThe intestine is made up of repetitive units that consist of a differentiated compartment (the villus) and a proliferative compartment (the crypt). Intestinal stem cells are located in the crypt (1, 2) and produce rapidly proliferating daughter cells, the transit amplifying cells, which subsequently differentiate into 2 main epithelial lineages. The absorptive lineage is composed of all enterocytes, while the secretory lineage is composed of goblet cells (secreting protective mucins), enteroendocrine cells (secreting hormones like serotonin or secretin), and Paneth cells (3, 4). Whether transit amplifying cells differentiate along an absorptive or a secretory lineage is regulated by the Notch pathway (5). Engagement of Notch receptors by Notch ligands, such as Delta or Jagged, induces proteolytic cleavage of the receptor by γ-secretase. The cleaved NOTCH1 receptor (NICD1) translocates into the nucleus, resulting in the formation of an active transcriptional complex composed of RBPJκ (also known as CSL or CBF1) and NICD1. Notch signal activation induces hairy/enhancer of split (Hes) gene expression. Ablation of Notch signaling via genetic deletion of Rbpj results in secretory cell expansion (6). Conversely, in transgenic mice overexpressing NICD1, goblet cells are absent, and the proliferative compartment is expanded (7).The Wnt signaling pathway is a key regulator of intestinal stem cell homeostasis (8), and 2 of the target genes induced by Wnt signaling, c-MYC and c-JUN, encode transcription factors that have oncogenic potential (9, 10). Consequently, aberrant activation of the adenomatous polyposis coli/β-catenin/T cell factor (APC/ β-catenin/TCF) pathway is an initiating event in the majority of human colorectal cancers (11).c-MYC is a transcription factor with key functions in cell differentiation and cancer development (12)(13)(14). In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15-18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19-21). c-MYC ubiquitination is antagonized by the deubiquitinase USP28, which "piggybacks" on FBW7 and stabilizes c-MYC protein (22). Thus, an E3 ubiquitin ligase and a deubiquitinase, FBW7 and USP28, are together recruited to substrates (22), and a cycle of deubiquitination and ubiquitination controls c-MYC stability.Genomic data from human cancers suggest that most colorectal cancer mutations converge on c-MYC misregulation (23). Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24-29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17). Transgenic expression of a dominant-negative allele of Myc, OmoMyc, has provided proof of principle that targeting ...

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Section: Discussionmentioning

confidence: 99%

“…In the intestine, c-MYC is required for the altered proliferation and differentiation induced by APC inactivation (15)(16)(17)(18). c-MYC is a highly labile protein, and at least 2 ubiquitin ligases, SKP2 and FBW7, can target it for proteasomal degradation (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Diefenbacher¹,

Popov

Blake³

et al. 2014

J. Clin. Invest.

127

141

View full text Add to dashboard Cite

show abstract

“…Of these target genes, the proto-oncogene Myc (He et al, 1998) appears to be of central importance, as co-deletion of both Apc and Myc within the murine intestinal epithelium rescues this 'crypt progenitor cell-like' phenotype. Concordantly, many of the Wnt targets deregulated after APC loss revert back to wild-type levels in double knockout APC Myc intestinal enterocytes (Ignatenko et al, 2006;Sansom et al, 2007).…”

mentioning

confidence: 95%

“…Given that the major function of c-Myc is as a transcriptional activator and repressor, we next investigated the expression of a number of Wnt target genes that are deregulated after APC loss (Sansom et al, 2004(Sansom et al, , 2007. Importantly, we have shown that the expression of these targets are returned to wild-type levels in double knockout Apc and Myc intestines (Sansom et al, 2007). Figure 2d shows the expression of 12 Wnt target genes in AhCre þ Apc fl/fl Myc þ / þ and AhCre þ Apc fl/fl Myc fl/ þ intestines four days after Cre induction.…”

mentioning

confidence: 99%

“…These studies also highlight the cooperation between Wnt and c-Myc in colorectal cancer. It should be noted that an activation of c-Myc alone is not sufficient to drive the intestinal phenotypes equivalent to APC loss, instead in APC-deficient cells c-Myc is essential (Sansom et al, 2007;Murphy et al, 2008). Indeed, a recent study (Finch et al, 2009) shows that very high expression of c-Myc could only recapitulate a subset of the phenotypes of Apc loss and target gene activation.…”

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Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

Athineos

Sansom

2010

Oncogene

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RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells

et al. 2022

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Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461‐induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC‐interacting zinc‐finger protein 1 (MIZ1)‐ and retinoblastoma protein (Rb)‐dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine‐ and patient‐derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.

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Myc deletion rescues Apc deficiency in the small intestine

Cited by 535 publications

References 23 publications

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells

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