HDAC and Hsp90 inhibitors down‐regulate PTTG1/securin but do not induce aneuploidy

Abstract

Human securin regulates correct chromatid separation. However, there are conflicting reports on the aneugenic effects of its gene deletion. Here we show that PTTG1/securin gene expression is dramatically repressed when Hsp90 or histone deacetylases are inhibited. However, these treatments do not increase the proportion of aneuploid cells. This was also confirmed using RNAi (silencing of PTTG1/securin > or =80%). As expected, histone deacetylases arrested cells in both G1 and G2. However, sec(-/-) HCT116 cells showed a greater disposition to arrest cells in G2 than sec(+/+) cells due to insufficient induction of CDKN1A. These results indicate that chromatid separation is controlled through redundant mechanisms and reveal a new aspect of securin in cell cycle regulation.

Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells

“…Previous studies have shown that HDAC inhibitors repress PTTG1 mRNA levels in a manner similar to Hsp90 inhibitors [11]. In the present study, we found that TSA gradually decreased PTTG1 mRNA levels in AtT-20 cells, similar to the Hsp90 inhibitors 17-AAG and CCT018159 [12].…”

“…The modification of histone acetylation plays an important role in controlling PTTG1 expression. Histone deacetylase (HDAC) inhibitors suppress PTTG1 mRNA levels in a manner similar to Hsp90 inhibitors [11].…”

“…Heat shock protein 90 (Hsp90) is an essential molecular chaperone involved in the folding and stabilization of client proteins which regulate the survival of cancer cells. Hsp90 inhibitors have been reported to repress PTTG1 expression in carcinoma cells [10,11], and are thought to act in a similar way in pituitary tumor cells. Previous studies have demonstrated that Hsp90 inhibitors decreased POMC mRNA and ACTH levels in AtT-20 cells [12,13].…”

Inorganic Pyrophosphatase Defects Lead to Cell Cycle Arrest and Autophagic Cell Death through NAD+ Depletion in Fermenting Yeast

“…Flow Cytometry and Microscopy-Cells were stained with propidium iodide essentially as described by Sazer and Sherwood (22) and analyzed on a Coulter Epics XL apparatus as described (23).…”

Inhibition of heat shock protein 90 decreases ACTH production and cell proliferation in AtT-20 cells

“…Geldanamycin, an ansamycin benzoquinone antibiotic and Hsp90 inhibitor, has shown antitumor effects in various tumor cells. Hsp90 inhibitors reportedly repress PTTG1 expression in carcinoma cells [17,18], and they are expected to act on pituitary tumor cells. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) (IC 50 = 7.2 lM) is a less toxic and potent synthetic derivative of geldanamycin.…”