The NKX3-1 gene is a homeobox gene required for prostate tumor progression, but how it functions is unclear. Here, using chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) we showed that NKX3-1 colocalizes with the androgen receptor (AR) across the prostate cancer genome. We uncovered two distinct mechanisms by which NKX3-1 controls the AR transcriptional network in prostate cancer. First, NKX3-1 and AR directly regulate each other in a feed-forward regulatory loop. Second, NKX3-1 collaborates with AR and FoxA1 to mediate genes in advanced and recurrent prostate carcinoma. NKX3-1-and AR-coregulated genes include those found in the "protein trafficking" process, which integrates oncogenic signaling pathways. Moreover, we demonstrate that NKX3-1, AR, and FoxA1 promote prostate cancer cell survival by directly upregulating RAB3B, a member of the RAB GTPase family. Finally, we show that RAB3B is overexpressed in prostate cancer patients, suggesting that RAB3B together with AR, FoxA1, and NKX3-1 are important regulators of prostate cancer progression. Collectively, our work highlights a novel hierarchical transcriptional regulatory network between NKX3-1, AR, and the RAB GTPase signaling pathway that is critical for the genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer.

Transcriptional corepressors are frequently aberrantly over-expressed in prostate cancers. However, their crosstalk with the Androgen receptor (AR), a key player in prostate cancer development, is unclear. Using ChIP-Seq, we generated extensive global binding maps of AR, ERG, and commonly over-expressed transcriptional corepressors including HDAC1, HDAC2, HDAC3, and EZH2 in prostate cancer cells. Surprisingly, our results revealed that ERG, HDACs, and EZH2 are directly involved in androgen-regulated transcription and wired into an AR centric transcriptional network via a spectrum of distal enhancers and/or proximal promoters. Moreover, we showed that similar to ERG, these corepressors function to mediate repression of AR-induced transcription including cytoskeletal genes that promote epithelial differentiation and inhibit metastasis. Specifically, we demonstrated that the direct suppression of Vinculin expression by ERG, EZH2, and HDACs leads to enhanced invasiveness of prostate cancer cells. Taken together, our results highlight a novel mechanism by which, ERG working together with oncogenic corepressors including HDACs and the polycomb protein, EZH2, could impede epithelial differentiation and contribute to prostate cancer progression, through directly modulating the transcriptional output of AR.

The measurement of gait parameters normally requires motion tracking systems combined with force plates, which limits the measurement to laboratory settings. In some recent studies, the possibility of using the portable, low cost, and marker-less Microsoft Kinect sensor to measure gait parameters on over-ground walking has been examined. The current study further examined the accuracy level of the Kinect sensor for assessment of various gait parameters during treadmill walking under different walking speeds. Twenty healthy participants walked on the treadmill and their full body kinematics data were measured by a Kinect sensor and a motion tracking system, concurrently. Spatiotemporal gait parameters and knee and hip joint angles were extracted from the two devices and were compared. The results showed that the accuracy levels when using the Kinect sensor varied across the gait parameters. Average heel strike frame errors were 0.18 and 0.30 frames for the right and left foot, respectively, while average toe off frame errors were -2.25 and -2.61 frames, respectively, across all participants and all walking speeds. The temporal gait parameters based purely on heel strike have less error than the temporal gait parameters based on toe off. The Kinect sensor can follow the trend of the joint trajectories for the knee and hip joints, though there was substantial error in magnitudes. The walking speed was also found to significantly affect the identified timing of toe off. The results of the study suggest that the Kinect sensor may be used as an alternative device to measure some gait parameters for treadmill walking, depending on the desired accuracy level.

Oestrogen receptor a (ERa) is key player in the progression of breast cancer. Recently, the cistrome and interactome of ERa were mapped in breast cancer cells, revealing the importance of spatial organization in oestrogenmediated transcription. However, the underlying mechanism of this process is unclear. Here, we show that ERa binding sites (ERBS) identified from the Chromatin Interaction Analysis-Paired End DiTag of ERa are enriched for AP-2 motifs. We demonstrate the transcription factor, AP-2c, which has been implicated in breast cancer oncogenesis, binds to ERBS in a ligand-independent manner. Furthermore, perturbation of AP-2c expression impaired ERa DNA binding, long-range chromatin interactions, and gene transcription. In genome-wide analyses, we show that a large number of AP-2c and ERa binding events converge together across the genome. The majority of these shared regions are also occupied by the pioneer factor, FoxA1. Molecular studies indicate there is functional interplay between AP-2c and FoxA1. Finally, we show that most ERBS associated with long-range chromatin interactions are colocalized with AP-2c and FoxA1. Together, our results suggest AP-2c is a novel collaborative factor in ERa-mediated transcription.

No abstract

No abstract

a b s t r a c tInertial motion capture (IMC) systems have become increasingly popular for ambulatory movement analysis. However, few studies have attempted to use these measurement techniques to estimate kinetic variables, such as joint moments and ground reaction forces (GRFs).Therefore, we investigated the performance of a full-body ambulatory IMC system in estimating 3D L5/S1 moments and GRFs during symmetric, asymmetric and fast trunk bending, performed by nine male participants. Using an ambulatory IMC system (Xsens/MVN), L5/S1 moments were estimated based on the upper-body segment kinematics using a top-down inverse dynamics analysis, and GRFs were estimated based on full-body segment accelerations.As a reference, a laboratory measurement system was utilized: GRFs were measured with Kistler force plates (FPs), and L5/S1 moments were calculated using a bottom-up inverse dynamics model based on FP data and lower-body kinematics measured with an optical motion capture system (OMC). Correspondence between the OMCþ FP and IMC systems was quantified by calculating root-mean-square errors (RMSerrors) of moment/force time series and the interclass correlation (ICC) of the absolute peak moments/forces.Averaged over subjects, L5/S1 moment RMSerrors remained below 10 Nm (about 5% of the peak extension moment) and 3D GRF RMSerrors remained below 20 N (about 2% of the peak vertical force). ICCs were high for the peak L5/S1 extension moment (0.971) and vertical GRF (0.998). Due to lower amplitudes, smaller ICCs were found for the peak asymmetric L5/S1 moments (0.690-0.781) and horizontal GRFs (0.559-0.948).In conclusion, close correspondence was found between the ambulatory IMC-based and laboratory-based estimates of back load.

No abstract