The MYC oncogene is a transcription factor whose overexpression is thought to induce tumorigenesis by causing inappropriate gene expression that results in autonomous cellular proliferation and a block in cellular differentiation. Recently, we have found that even the brief inactivation of the MYC oncogene can result in the sustained loss of a neoplastic phenotype. We demonstrated that upon MYC inactivation immature osteogenic sarcoma cells differentiated into mature osteocytes and formed bone. Surprisingly, MYC reactivation failed to restore a neoplastic phenotype and instead induced the now differentiated tumor cells to undergo apoptosis. Our results suggest to us the interesting possibility that MYC inactivation causes the loss of a neoplastic phenotype by inducing tumors to differentiate. In this new epigenetic context, the ability of the MYC oncogene to induce the expression of genes responsible for sustaining cellular proliferation and hence tumorigenesis has been revoked and now instead apoptosis occurs. We hypothesize, that upon differentiation the tumor cells undergo chromatin remodeling and this new epigenetic program prevents MYC from inducing the transcription of genes required to induce or sustain tumorigenesis. Instead, MYC activation induces apoptosis. To examine for this possibility, we propose: to determine the duration of MYC inactivation required to result in sustained loss of a neoplastic phenotype by time lapsed video microscopy; to determine if the ability of MYC to activate the transcription of different gene targets changes upon differentiation of tumor cells by examining the expression of specific target genes by RT-PCR and global changes in gene expression by cDNA microarrays and by measuring the accessibility of specific target gene loci to MYC binding by chromatin immunoprecipitation and histone acetylation; and to determine if the ability of MYC to induce apoptosis changes upon the differentiation of tumor cells by examining the change in expression patterns of both pro- and anti-apoptotic gene products and by directly determining the effects of the inhibition of apoptotic pathways. The results of our experiments may have important implications for how the state of differentiation of a cell influences the ability of MYC to induce gene expression and thereby initiate and sustain tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA105102-04
Application #
7173835
Study Section
Pathology B Study Section (PTHB)
Program Officer
Spalholz, Barbara A
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$316,462
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Shroff, Emelyn H; Eberlin, Livia S; Dang, Vanessa M et al. (2015) MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci U S A 112:6539-44
Casey, Stephanie C; Vaccari, Monica; Al-Mulla, Fahd et al. (2015) The effect of environmental chemicals on the tumor microenvironment. Carcinogenesis 36 Suppl 1:S160-83
Casey, Stephanie C; Amedei, Amedeo; Aquilano, Katia et al. (2015) Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin Cancer Biol 35 Suppl:S199-S223
Gabay, Meital; Li, Yulin; Felsher, Dean W (2014) MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring Harb Perspect Med 4:
Li, Y; Casey, S C; Felsher, D W (2014) Inactivation of MYC reverses tumorigenesis. J Intern Med 276:52-60
Ansari, Celina; Tikhomirov, Grigory A; Hong, Su Hyun et al. (2014) Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small 10:566-75, 417
Casey, Stephanie C; Li, Yulin; Felsher, Dean W (2014) An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation. Immunol Res 58:282-91
Casey, Stephanie C; Bellovin, David I; Felsher, Dean W (2013) Noncanonical roles of the immune system in eliciting oncogene addiction. Curr Opin Immunol 25:246-58
Bisikirska, B C; Adam, S J; Alvarez, M J et al. (2013) STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma. Oncogene 32:5283-91
Rakhra, Kavya; Felsher, Dean W (2013) Generation of a tetracycline regulated mouse model of MYC-induced T-cell acute lymphoblastic leukemia. Methods Mol Biol 1012:221-35

Showing the most recent 10 out of 33 publications