Tea domain transcription factor TEAD4 mitigatesTGF-β signaling and hepatocellular carcinomaprogression independently of YAP

Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yesassociated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforminggrowth factor-β (TGF-β)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 playsa YAP-independent role in TGF-β signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer viamitigating TGF-β signaling. Ectopic TEAD4 inhibited TGF-β-induced signal transduction, Smad transcriptional activity, and targetgene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenografttumorgrowth in mice. Consistently, depletion of endogenous TEAD4 by siRNAs enhanced TGF-β signaling in cancer cells. Mechanistically,TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing the binding of Smad2/3to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-β/Smad signaling are independent ofYAP, as impairing the TEAD4–YAP interaction through point mutagenesis or depletion of YAP and/or its paralog TAZ has little effect.Together, these results unravel a novel function of TEAD4 in fine tuning TGF-β signaling and liver cancer progression in a YAPindependent manner.

Regulation of the cell fate by DNA damage and hypoxia

In order to provide the means for the design of novel rational anti-cancer drug therapies research efforts are concentrated on unravelling the molecular circuits which induce programmed cell death and block proliferation of cancer cells.Modern therapeutic strategies are based on the understanding of the complexity of physiological functions such as differentiation,development,immune responses,cell-cycle arrest,DNA damage repair,apoptosis,autophagy,energy metabolism,and senescence.It has become evident that this knowledge will provide the means to target the components of the pathways involved in these processes in a specific and selective manner thus paving the way for the development of effective and personalised anti-cancer therapies.Transcription is a crucial cellular process that regulates a multitude of physiological functions,which are essential in disease progression and cellular response to therapy.Transcription factors such as the p53 tumor suppressor and the hypoxia-inducible factor-α(HIF-α) are key players in carcinogenesis and cellular response to cancer therapies.Both of these transcription factors regulate gene expression of genes involved in cell death and proliferation,in some cases cooperating towards producing the same outcome and in some others mediating opposing effects.It is thus apparent that fine tuning of the activity of these transcription factors is essential to determine the cellular response to therapeutic regimens,in other words whether tumor cells will commit to apoptosis or evade engagement with the anti-proliferative effects of drugs leading to drug resistance.Our observations support the notion that the functional crosstalk between HIF-1α and p53 pathways and thus the fine tuning of their transcriptional activity is mediated by cofactors shared between the two transcription factors such as components of the p300 co-activator multiprotein complex.In particular,there is evidence to suggest that differential composition of the co-modulatory protein complexes associated with p53 and HIF-la under diverse types of stress conditions differentially regulate the expression of distinct subsets of p53 and HIF-la target genes involved in processes such as cell cycle arrest,apoptosis,chronic inflammation,and cellular energy metabolism thereby determining the cellular fate under particular types of microenvironmental stress.

Histone acetyltransferase p300 regulates the expression of human pituitary tumor transforming gene (hPTTG)

The human pituitary tumor transforming gene （hPTTG） serves as a marker for malignancy grading in several cancers, hPTTG is involved in multiple cellular pathways including cell transformation, apoptosis, DNA repair, genomic instability, mitotic control and angiogenesis induction. However, the molecular mechanisms underlying hPTTG regulation have not been fully explored. In this study, we found that overexpression of histone acetyltransferase （HAT） p300 upregulated hPTTG at the levels of promoter activity, mRNA and protein expression. Moreover, the HAT activity of p300 was critical for its regulatory function. Chromatin immunoprecipitation （CHIP） analysis revealed that overexpression of p300 elevated the level of histone H3 acetylation on the hPTTG promoter. Additionally, the NF-Y sites at the hPTTG promoter exhibited a synergistic effect on upregulation of hPTTG through interacting with p300. We also found that treatment of 293T cells with the histone deacetylase （HDAC） inhibitor Tfichostatin A （TSA） increased hPTTG promoter activity. Meanwhile, we provided evidence that HDAC3 decreased hPTTG promoter activity. These data implicate an important role of the histone acetylafion modification in the regulation of hPTTG.