No abstract

Cell senescence, an irreversible cell cycle arrest, reflects a safeguard program that limits the capacity of uncontrolled cell proliferation. Treatment of tumor cells with certain chemotherapeutic agents activates premature senescence to decrease the tumorigenecity. Here we show that sublethal concentrations of adriamycin could induce premature senescence in lung cancer cells. Adriamycin treatment resulted in the up-regulation of BMP4, which is underexpressed in NSCLC (non-small cell lung cancers). Moreover, the BMP4-Smad pathway played a key role in mediating adriamycin-induced senescence. Overexpression of BMP4 was able to induce premature senescence in lung cancer cells and this process required the participation of cyclin/ cyclin-dependent kinase (cdk) inhibitors p16INK4a and p21 WAF1/cip1 . We also show that increases of p16 INK4a and p21 WAF1/cip1 expression in response to BMP4 were mediated by the Smad signaling pathway. Furthermore, our data revealed that p300 was recruited to P16 INK4a and P21 WAF1/cip1 promoters by Smad1/5/8 to induce the hyperacetylation of histones H3 and H4 at the promoters. The present study provides useful clues to the evaluation of the potentiality of BMP4 as a responsive molecular target for cancer chemotherapy.

The transcription factor YY1 has been implicated to play a role in cell growth control. In this report, we demonstrate that YY1 was able to suppress NCI-H460 cell senescence through regulating the expression of p16(INK4a), a cyclin-dependent kinase inhibitor. We also show that YY1 participated in the repression of p16(INK4a) expression in 293T cells through an epigenetic mechanism involving histone acetylation modification. Specifically, HDAC3 and HDAC4 inhibited the p16(INK4a) promoter activity. The chromatin immunoprecipitation (ChIP) assays verified that HDAC3 and HDAC4 were recruited to p16(INK4a) promoter by YY1. Moreover, co-immunoprecipitation assays revealed that these three protein factors formed a complex. Furthermore, knockdown of these factors induced cell enlargement and flattened morphology and significantly increased the SA-beta-gal activity, a biochemical marker of cell senescence. Overall, data from this study suggest that YY1, HDAC3 and HDAC4 restrained cell senescence by repressing p16(INK4a) expression through an epigenetic modification of histones.

No abstract

All-trans retinoic acid (ATRA) has been widely investigated for treatments of many cancers including prostate cancer. HOXB13, silenced in androgen receptor-negative (AR−) prostate cancer cells, plays a role in AR− prostate cancer cell growth arrest. In this study we intended to elucidate the mechanisms that are involved in the proliferation inhibition of AR− prostate cancer cells triggered by ATRA. We discovered that ATRA was able to induce the growth arrest and to increase HOXB13 expression in AR− prostate cancer cells. Both EZH2 and DNMT3b participated in the repression of HOXB13 expression through an epigenetic mechanism involving DNA and histone methylation modifications. Specifically, EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. Moreover, ATRA could upregulate HOXB13 through decreasing EZH2 and DNMT3b expressions and reducing their interactions with the HOXB13 promoter. Concurrently, the methylation level of the HOXB13 promoter was reduced upon the treatment of ATRA. Results from this study implicated a novel effect of ATRA in inhibition of the growth of AR− resistant human prostate cancer cells through alteration of HOXB13 expression as a result of epigenetic modifications.