Atxn7, a subunit of SAGA chromatin remodeling complex, is subject to polyglutamine expansion at the amino terminus, causing spinocerebellar ataxia type 7 (SCA7), a progressive retinal and neurodegenerative disease. Within SAGA, the Atxn7 amino terminus anchors Non-stop, a deubiquitinase, to the complex. To understand the scope of Atxn7-dependent regulation of Non-stop, substrates of the deubiquitinase were sought. This revealed Non-stop, dissociated from Atxn7, interacts with Arp2/3 and WAVE regulatory complexes (WRC), which control actin cytoskeleton assembly. There, Non-stop countered polyubiquitination and proteasomal degradation of WRC subunit SCAR. Dependent on conserved WRC interacting receptor sequences (WIRS), Non-stop augmentation increased protein levels, and directed subcellular localization, of SCAR, decreasing cell area and number of protrusions. In vivo, heterozygous mutation of SCAR did not significantly rescue knockdown of Atxn7, but heterozygous mutation of Atxn7 rescued haploinsufficiency of SCAR.

Obesity creates a localized inflammatory reaction in the adipose, altering secretion of adipocyte-derived factors that contribute to pathologies including cancer. We have previously shown that adiponectin inhibits pancreatic cancer by antagonizing leptin-induced STAT3 activation. Yet, the effects of adiponectin on pancreatic cancer cell metabolism have not been addressed. In these studies, we have uncovered a novel metabolic function for the synthetic adiponectin-receptor agonist, AdipoRon. Treatment of PDAC cells with AdipoRon led to mitochondrial uncoupling and loss of ATP production. Concomitantly, AdipoRon-treated cells increased glucose uptake and utilization. This metabolic switch further correlated with AMPK mediated inhibition of the prolipogenic factor acetyl coenzyme A carboxylase 1 (ACC1), which is known to initiate fatty acid catabolism. Yet, measurements of fatty acid oxidation failed to detect any alteration in response to AdipoRon treatment, suggesting a deficiency for compensation. Additional disruption of glycolytic dependence, using either a glycolysis inhibitor or low-glucose conditions, demonstrated an impairment of growth and survival of all pancreatic cancer cell lines tested. Collectively, these studies provide evidence that pancreatic cancer cells utilize metabolic plasticity to upregulate glycolysis in order to adapt to suppression of oxidative phosphorylation in the presence of AdipoRon.

Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated sensory neuron-specific, Advillin-Cre knockout of Oxct1 (SNACKO) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and innervation of the skin and spinal dorsal horn. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. SNACKO mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet SNACKO mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.

Adipocytes are the most abundant cell type in the adipose tissue, and their dysfunction is a significant driver of obesity-related pathologies, such as cancer. The mechanisms that (1) drive the maintenance and secretory activity of adipocytes and (2) mediate the cancer cellular response to the adipocyte-derived factors are not fully understood. To address that gap of knowledge, we investigated how alterations in Src homology region 2-containing protein (SHP2) activity affect adipocyte function and tumor crosstalk. We found that phospho-SHP2 levels are elevated in adipose tissue of obese mice, obese patients, and differentiating adipocytes. Immunofluorescence and immunoprecipitation analyses as well as in-silico protein–protein interaction modeling demonstrated that SHP2 associates with PDHA1, and that a positive association promotes a reactive oxygen species (ROS)-driven adipogenic program. Accordingly, this SHP2-PDHA1-ROS regulatory axis was crucial for adipocyte maintenance and secretion of interleukin-6 (IL-6), a key cancer-promoting cytokine. Mature adipocytes treated with an inhibitor for SHP2, PDHA1, or ROS exhibited an increased level of pro-lipolytic and thermogenic proteins, corresponding to an increased glycerol release, but a suppression of secreted IL-6. A functional analysis of adipocyte-cancer cell crosstalk demonstrated a decreased migration, invasion, and a slight suppression of cell cycling, corresponding to a reduced growth of pancreatic cancer cells exposed to conditioned media (CM) from mature adipocytes previously treated with inhibitors for SHP2/PDHA1/ROS. Importantly, PDAC cell growth stimulation in response to adipocyte CM correlated with PDHA1 induction but was suppressed by a PDHA1 inhibitor. The data point to a novel role for (1) SHP2-PDHA1-ROS in adipocyte maintenance and secretory activity and (2) PDHA1 as a regulator of the pancreatic cancer cells response to adipocyte-derived factors.