SOX7 induced G1 to S phase arrest by down-regulation of cyclin D1 and c-myc.

<p>(A) Western blotting analysis of SOX7, cyclin D1, c-myc and GAPDH levels in SMMC-7721 and Hep3B cells transfected with vector or SOX7. (B, C) Overexpression of cyclin D1 and c-myc could override G1 to S pahse arrest induced by SOX7. Cyclin D1 or c-myc was overexpressed in SOX7-overexpression cells, and the cell percentages in G0/G1, S and G2/M phase were measured by flow cytometric analysis. * indicates <i>p</i><0.05. The experiments were performed independently three times at least.</p

Relationship between SOX7 expression and clinicopathologic features of patients with hepatocellular carcinoma.

<p>Relationship between SOX7 expression and clinicopathologic features of patients with hepatocellular carcinoma.</p

Overexpression of SOX7 inhibited cell cycle.

<p>(A) Representative pictures of flow cytometric analysis of SMMC-7721cells transfected with vector or SOX7. (B) The cell percentages in G0/G1, S and G2/M phase were measured. (C) Representative pictures of flow cytometric analysis of Hep3B cells transfected with vector or SOX7. (D) The cell percentages in G0/G1, S and G2/M phase were measured. * indicates <i>p</i><0.05. The experiments were performed independently three times at least.</p

HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells

Activator protein 1 (AP-1) is a transcriptional factor composed of the dimeric members of bZIP proteins, which are frequently deregulated in human cancer cells. In this study, we aimed to identify an oncogenic AP-1 dimer critical for the proliferation of neuroblastoma cells and to investigate whether histone deacetylase inhibitors (HDACIs), a new generation of anticancer agents, could target the AP-1 dimer. We report here that HDACIs including trichostatin A, suberoylanilidehydroxamic acid, valproic acid and M344 can transcriptionally suppress both c-Jun and Fra-1, preceding their inhibition of cell growth. c-Jun preferentially interacting with Fra-1 as a heterodimer is responsible for AP-1 activity and critical for cell growth. Mechanistically, HDACIs suppress Fra-1 expression through transcriptionally downregulating Raf1 and subsequently decreasing MEK1/2-ERK1/2 activity. Unexpectedly, HDACI treatment caused MKK7 downregulation at both the protein and mRNA levels. Deletion analysis of the 5′-flanking sequence of the MKK7 gene revealed that a major element responsible for the downregulation by HDACI is located at -149 to -3 relative to the transcriptional start site. Knockdown of MKK7 but not MKK4 remarkably decreased JNK/c-Jun activity and proliferation, whereas ectopic MKK7-JNK1 reversed HDACI-induced c-Jun suppression. Furthermore, suppression of both MKK-7/c-Jun and Raf-1/Fra-1 activities was involved in the tumor growth inhibitory effects induced by SAHA in SH-SY5Y xenograft mice. Collectively, these findings demonstrated that c-Jun/Fra-1 dimer is critical for neuroblastoma cell growth and that HDACIs act as effective suppressors of the two oncogenes through transcriptionally downregulating MKK7 and Raf1