The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

International audienceHeparan sulfate (HS) proteoglycan chains are key components of the breast tumor microenvironment that critically influence the behavior of cancer cells. It is established that abnormal synthesis and processing of HS play a prominent role in tumorigenesis, albeit mechanisms remain mostly obscure. HS function is mainly controlled by sulfotransferases, and here we report a novel cellular and pathophysiological significance for the 3-O-sulfotransferase 3-OST3A (HS3ST3A), catalyzing the final maturation step of HS, in breast cancer. We show that 3-OST3A is epigenetically repressed in all breast cancer cell lines of a panel representative of distinct molecular subgroups, except in human epidermal growth factor receptor 2-positive (HER2+) sloan-kettering breast cancer (SKBR3) cells. Epigenetic mechanisms involved both DNA methylation and histone modifications, producing different repressive chromatin environments depending on the cell molecular signature. Gain and loss of function experiments by cDNA and siRNA transfection revealed profound effects of 3-OST3A expression on cell behavior including apoptosis, proliferation, response to trastuzumab in vitro and tumor growth in xenografted mice. 3-OST3A exerted dual activities acting as tumor-suppressor in lumA-michigan cancer foundation (MCF)-7 and triple negative-MD Anderson (MDA) metastatic breast (MB)-231 cells, or as an oncogenic factor in HER2+-SKBR3 cells. Mechanistically, fluorescence-resonance energy transfer-fluorescence-lifetime imaging microscopy experiments indicated that the effects of 3-OST3A in MCF-7 cells were mediated by altered interactions between HS and fibroblast growth factor-7 (FGF-7). Further, this interplay between HS and FGF-7 modulated downstream ERK, AKT and p38 cascades, suggesting that altering 3-O-sulfation affects FGFR2IIIb-mediated signaling. Corroborating our cellular data, a clinical study conducted in a cohort of breast cancer patients uncovered that, in HER2+ patients, high level expression of 3-OST3A in tumors was associated with reduced relapse-free survival. Our findings define 3-OST3A as a novel regulator of breast cancer pathogenicity, displaying tumor-suppressive or oncogenic activities in a cell-and tumor-dependent context, and demonstrate the clinical value of the HS-O-sulfotransferase 3-OST3A as a prognostic marker in HER2+ patients

Phase-Dependent Suppression of Beta Oscillations in Parkinson's Disease Patients

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain

'Click'-xylosides as initiators of the biosynthesis of glycosaminoglycans : Comparison of mono-xylosides with xylobiosides.

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Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus

Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing