Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression

Zhang, Xiaoli; Farrell, Amy; Daniel, Colin J.; Arnold, Hugh; Scanlan, Charles; Laraway, Bryan; Janghorban, Mahnaz; Lum, Lawrence; Chen, Dexi; Troxell, Megan L.; Sears, Rosalie C.

doi:10.1073/pnas.1100764108

Cited by 72 publications

(97 citation statements)

References 38 publications

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“…Previously, we have shown that pS62-MYC, a more stable and active form of MYC, is highly expressed in breast cancers (4,7). In addition, we found that expression of AXIN1, which nucleates the MYC degradation complex, is decreased in some breast tumors (4).…”

Section: Resultsmentioning

confidence: 72%

“…In addition, we found that expression of AXIN1, which nucleates the MYC degradation complex, is decreased in some breast tumors (4). To investigate additional mechanisms that lead to MYC overexpression, we focused on SET and CIP2A, two oncogenic cellular inhibitors of PP2A, the phosphatase that removes S62 phosphorylation to destabilize MYC.…”

Section: Resultsmentioning

confidence: 99%

“…Western blot, ChIP, and IF analyses were performed as described previously (4,11,12) and as detailed in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…S1B) was provided by Dexi Chen (Department of Infectious Diseases, Capital University of Medical Sciences, You'an Hospital, Beijing) and described in ref. 4.…”

Section: Methodsmentioning

confidence: 99%

“…Expression of MYC is regulated at multiple levels, including protein stability, which is increased in several cancer types (1,3,4). MYC stability is regulated in part by sequential and interdependent phosphorylation at two conserved residues, threonine 58 (T58) and serine 62 (S62) (5).…”

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confidence: 99%

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Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Janghorban¹,

Farrell²,

Allen-Petersen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.breast cancer therapy | phosphatase activator T he c-MYC (MYC) oncoprotein is overexpressed in human breast cancer and this is associated with poor clinical outcome (1, 2). Expression of MYC is regulated at multiple levels, including protein stability, which is increased in several cancer types (1,3,4). MYC stability is regulated in part by sequential and interdependent phosphorylation at two conserved residues, threonine 58 (T58) and serine 62 (S62) (5). MYC is phosphorylated at S62 (pS62) through the mitogen-activated protein kinase (MAPK) pathway or cyclin-dependent kinase (CDK) activation in response to growth signals and this modification increases its stability and oncogenic activity (5-8). When growth signals cease, GSK3, in a manner dependent upon prior phosphorylation at S62, phosphorylates T58 (pT58) (5, 6). T58 phosphorylation facilitates protein phosphatase 2A (PP2A)-mediated dephosphorylation of pS62 and recruitment of the E3 ubiquitin ligase SCF Fbw7 to initiate proteasomal destruction of MYC (9, 10). This process is facilitated by AXIN1, which helps nucleate a destruction complex for MYC at target gene promoters (11, 12). Our previous work has shown that MYC stability is increased in breast cancers and that this correlates with high pS62-and low pT58-MYC (4).PP2A is a ubiquitously expressed, heterotrimeric serinethreonine (S/T) phosphatase that mediates 30-50% of cellular S/T phosphatase activity (13). Target specificity of PP2A is directed by a variable regulatory (B) subunit, and we have shown that B56α is the isoform that directs PP2A to MYC (9, 13). Human cell transformation requires inhibition of PP2A activity and, in an siRNA screen, B56α, ...

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

“…Western blot, ChIP, and IF analyses were performed as described previously (4,11,12) and as detailed in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…S1B) was provided by Dexi Chen (Department of Infectious Diseases, Capital University of Medical Sciences, You'an Hospital, Beijing) and described in ref. 4.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Janghorban¹,

Farrell²,

Allen-Petersen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

168

175

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Hematological and neurological expressed 1 (HN1) activates c‐Myc signaling by inhibiting ubiquitin‐mediated proteasomal degradation of c‐Myc in hepatocellular carcinoma

Feng

Liu

Fang

et al. 2022

Cell Biology International

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Hepatocellular carcinoma (HCC) has a poor prognosis due to the usually advanced stage at diagnosis. Sustained activation of the MYC oncogene is implicated in the development of HCC; however, the molecular mechanisms of MYC deregulation in HCC are poorly understood. Here, real-time PCR and western blotting were used to measure the expression of hematological and neurological expressed 1 (HN1) in HCC cells. Expression of HN1 and MYC in clinical specimens was analyzed using immunohistochemistry. The role of HN1 in HCC proliferation, migration, and invasion was explored in vitro and in vivo. MYC expression was measured using realtime PCR and western blotting. MYC transcriptional activity was assessed using a luciferase reporter system. Expression of MYC target genes was quantified using real-time PCR. Protein interaction between MYC and HN1 was assessed using co-immunoprecipitation and western blotting. We identified HN1 as a novel regulatory factor of the glycogen synthase kinase (GSK) 3β-MYC axis. HN1 expression is elevated in liver tumor tissues and cells, and significantly correlates with poor survival in HCC patients. Upregulation of HN1 promotes, and silencing of HN1 represses, the proliferation and metastasis of liver cancer cells in vitro and in vivo. Moreover, our results demonstrate that HN1 sustains stabilization and persistent activity of MYC via interaction with GSK3β in HCC. Importantly, the tumor-promoting effects of HN1 on HCC cells were attenuated by suppressing MYC. In conclusion, constitutive activation of MYC by HN1 promotes the progression of HCC; therefore, HN1 might be a novel therapeutic target for HCC.

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Oncogenic activation of glypican-3 by c-Myc in human hepatocellular carcinoma

Jin

Zhang

et al. 2012

Hepatology

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Glypican-3 (GPC3) is a heparan sulfate proteoglycan that has an important role in cell growth and differentiation, and its function in tumorigenesis is tissue-dependent. In hepatocellular carcinoma (HCC), the overexpression of GPC3 has been demonstrated to be a reliable diagnostic indicator. However, the mechanisms that regulate the expression and function of GPC3 remain unclear. The oncoprotein c-Myc is a transcription factor that plays a significant role in more than 50% of human tumors. We report here that GPC3 is a transcriptional target of c-Myc and that the expression of c-Myc is also regulated by GPC3, thus forming a positive feedback signaling loop. We found that the overexpression of c-Myc could induce GPC3 promoter-dependent luciferase activity in luciferase reporter experiments. Furthermore, mutational analysis identified c-Myc-binding sites within the GPC3 promoter. The exogenous overexpression of c-Myc increased the endogenous messenger RNA (mRNA) and protein levels of GPC3. Chromatin immunoprecipitation experiments revealed the binding of c-Myc to the endogenous GPC3 promoter, indicating that c-Myc can directly transcriptionally activate GPC3. Interestingly, GPC3 can also elevate c-Myc expression. Overexpression of GPC3 increased c-Myc protein levels, whereas the knockdown of GPC3 reduced c-Myc expression levels. Lastly, the elevated levels of c-Myc correlate with the overexpression of GPC3 in human HCC samples. Conclusion: These data provide new mechanistic insight into the roles of GPC3 and of c-Myc in the development of HCC. (HEPATOLOGY 2012;56:1380-1390 P rimary hepatocellular carcinoma (HCC) is the world's fifth most common cancer, and the third most common cause of cancer deaths. 1 HCC is a common malignant tumor, and causes over 100,000 HCC deaths per year in China. 2 Only 10%-20% of total HCCs can be treated in the early stage by surgery. Most HCCs are diagnosed at late stages, and as a result they progress rapidly, are difficult to treat, and exhibit poor prognosis. Early diagnosis and treatment are critical factors for improving the survival of HCC patients.Recent research has shown that glypican-3 (GPC3) is a specific and sensitive biomarker for the diagnosis of HCC. 3 GPC3 is a proteoglycan that is localized on the cell surface. The abnormal expression of GPC3 in HCC was first reported by Hsu et al. 4 in 1997. In that study, 75% of HCC patients were found to overexpress GPC3 messenger RNA (mRNA), whereas patients with benign liver disease or normal livers exhibited no expression of GPC3 mRNA or protein. Soluble GPC3 protein can be detected in the serum of 50% of HCC patients, demonstrating its value as a diagnostic marker for HCC. 5 The expression of GPC3, its receptor, and of other growth factors coordinate signal transduction pathways that regulate cellular morphology and a variety of cellular behaviors, such as adhesion,

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Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression

Cited by 72 publications

References 38 publications

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer

Hematological and neurological expressed 1 (HN1) activates c‐Myc signaling by inhibiting ubiquitin‐mediated proteasomal degradation of c‐Myc in hepatocellular carcinoma

Oncogenic activation of glypican-3 by c-Myc in human hepatocellular carcinoma

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