G0S2 Suppresses Oncogenic Transformation by Repressing a MYC-Regulated Transcriptional Program

Abstract

Methylation-mediated silencing of 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 (MEFs). G0S2-null MEFs were readily transformed with HRAS or EGFR treatment compared to wildtype 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 that 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 to malignant tissue. Intriguingly, high levels of G0S2 were also associated with a decrease in breast cancer recurrence rates, especially in estrogen receptor-positive 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.

Heterogeneous nuclear ribonucleoprotein K is associated with poor prognosis and regulates proliferation and apoptosis in bladder cancer

“…Cyclin D1, a key regulator in G1‐to‐S‐phase transition, is overexpressed in bladder cancer and associated with poor prognosis . Several studies have revealed that G0S2 suppresses oncogenic transformation and induces apoptosis in cancer cells . These data strongly suggest that hnRNPK regulates the cell cycle of bladder cancer cells mainly by transcriptional regulation of cyclin D1 and G0S2.…”

Differential Gene Regulation and Tumor-Inhibitory Activities of Alpha-, Delta-, and Gamma-Tocopherols in Estrogen-Mediated Mammary Carcinogenesis

“…It inhibits cell growth, invasion and Akt activation (48). γ-T upregulated the tumor suppressor G0S2 which has been reported to inhibit oncogenic transformation through repression of Myc activity (49). Thus, treatment of ACI rats with γ-T regulated the expression of genes that control cell proliferation, ER-dependent signaling, apoptosis, tumor progression and metastasis.…”

Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease

“…4F). G0s2 may be involved in immunoregulation in autoimmune diseases, cancer, and metabolic syndrome (Nakamura et al, 2006; Yim et al, 2016, Yang et al, 2010, Zhang et al, 2014, Cristillo et al, 1997, Russell and Forsdyke, 1991). Thus, these results suggested that G0s2 expression may be important for the p65-dependent transcription of inflammation-related genes in wild-type 5/6Nx mice.…”