GOS2 suppresses oncogenic transformation by repressing a MYC-regulated transcriptional program

Christina Y. Yim, David J. Sekula, Mary P. Hever-Jardine, Xi Liu, Joshua M. Warzecha, Janice Tam, Sarah J. Freemantle, Ethan Dmitrovsky, Michael J. Spinella

Research output: Contribution to journalArticle

Abstract

Methylation-mediated silencing of G0-G1 switch gene 2 (G0S2) has been detected in a variety of solid tumors, whereas G0S2 induction is associated with remissions in patients with acute promyelocytic leukemia, implying that G0S2 may possess tumor suppressor activity. In this study, we clearly demonstrate that G0S2 opposes oncogene-induced transformation using G0s2-null immortalized mouse embryonic fibroblasts (MEF). G0s2-null MEFs were readily transformed with HRAS or EGFR treatment compared with wild-type MEFs. Importantly, restoration of G0S2 reversed HRAS-driven transformation. G0S2 is known to regulate fat metabolism by attenuating adipose triglyceride lipase (ATGL), but repression of oncogene-induced transformation by G0S2 was independent of ATGL inhibition. Gene expression analysis revealed an upregulation of gene signatures associated with transformation, proliferation, and MYC targets in G0s2-null MEFs. RNAi-mediated ablation and pharmacologic inhibition of MYC abrogated oncogene-induced transformation of G0s2-null MEFs. Furthermore, we found that G0S2 was highly expressed in normal breast tissues compared with malignant tissue. Intriguingly, high levels of G0S2 were also associated with a decrease in breast cancer recurrence rates, especially in estrogen receptorpositive subtypes, and overexpression of G0S2 repressed the proliferation of breast cancer cells in vitro. Taken together, these findings indicate that G0S2 functions as a tumor suppressor in part by opposing MYC activity, prompting further investigation of the mechanisms by which G0S2 silencing mediates MYC-induced oncogenesis in other malignancies.

Original languageEnglish (US)
Pages (from-to)1204-1213
Number of pages10
JournalCancer Research
Volume76
Issue number5
DOIs
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'GOS2 suppresses oncogenic transformation by repressing a MYC-regulated transcriptional program'. Together they form a unique fingerprint.

  • Cite this

    Yim, C. Y., Sekula, D. J., Hever-Jardine, M. P., Liu, X., Warzecha, J. M., Tam, J., Freemantle, S. J., Dmitrovsky, E., & Spinella, M. J. (2016). GOS2 suppresses oncogenic transformation by repressing a MYC-regulated transcriptional program. Cancer Research, 76(5), 1204-1213. https://doi.org/10.1158/0008-5472.CAN-15-2265