Antineoplastic effects of histone deacetylase inhibitors in neuroendocrine cancer cells are mediated through transcriptional regulation of Notch1 by activator protein 1.

Notch signaling is minimally active in neuroendocrine (NE) cancer cells. While histone deacetylase inhibitors (HDACi) suppress NE cancer growth by inducing Notch, the molecular mechanism underlying this interplay has not yet been defined. NE cancer cell lines BON, H727, and MZ-CRC-1 were treated with known HDACi Thailadepsin-A (TDP-A) and valproic acid (VPA), and Notch1 mRNA expression was measured with RT-PCR. Truncated genomic fragments of the Notch1 promotor region fused with luciferase reporter were used to identify the potential transcription factor (TF) binding site. The key regulatory TF was identified with the electrophoretic mobility shift assay (EMSA). The effect of HDACi on Notch1 level was determined before and after silencing the TF. TDP-A and VPA induced Notch1 mRNA in a dose-dependent manner. A functional DNA motif at -80 to -52 from the Notch1 start codon responsible for the HDACi-dependent Notch1 induction was identified. Mutation of this core sequence failed to induce luciferase activity despite HDACi treatment. EMSA showed the greatest gel shift with AP-1 in nuclear extracts. Knockdown of AP-1 significantly attenuated the effect of HDACi on Notch1 induction. Interestingly, AP-1 transfection did not alter Notch1 level, suggesting that AP-1 is necessary but insufficient for HDACi activation of Notch1. Therefore, AP-1 is the TF that binds to a specific transcription-binding site within the Notch1 promotor region to trigger Notch1 transcription. Elucidating the HDACi activation mechanism may lead to the development of novel therapeutic options against NE cancers and facilitate the identification of clinical responders and prevent adverse effects.

Fast Flexible Transistors with a Nanotrench Structure.

The simplification of fabrication processes that can define very fine patterns for large-area flexible radio-frequency (RF) applications is very desirable because it is generally very challenging to realize submicron scale patterns on flexible substrates. Conventional nanoscale patterning methods, such as e-beam lithography, cannot be easily applied to such applications. On the other hand, recent advances in nanoimprinting lithography (NIL) may enable the fabrication of large-area nanoelectronics, especially flexible RF electronics with finely defined patterns, thereby significantly broadening RF applications. Here we report a generic strategy for fabricating high-performance flexible Si nanomembrane (NM)-based RF thin-film transistors (TFTs), capable of over 100 GHz operation in theory, with NIL patterned deep-submicron-scale channel lengths. A unique 3-dimensional etched-trench-channel configuration was used to allow for TFT fabrication compatible with flexible substrates. Optimal device parameters were obtained through device simulation to understand the underlying device physics and to enhance device controllability. Experimentally, a record-breaking 38 GHz maximum oscillation frequency fmax value has been successfully demonstrated from TFTs with a 2 µm gate length built with flexible Si NM on plastic substrates.