Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival downstream of HER2-driven glucose uptake and metabolism.

Oncogenic reprogramming of cellular metabolism is a hallmark of many cancers, but our mechanistic understanding of how such dysregulation is linked to tumor behavior remains poor. In this study, we have identified dihydroceramide desaturase (DES1)-which catalyzes the last step in de novo sphingolipid synthesis-as necessary for the acquisition of anchorage-independent survival (AIS), a key cancer enabling biology, and establish DES1 as a downstream effector of HER2-driven glucose uptake and metabolism. We further show that DES1 is sufficient to drive AIS and in vitro tumorigenicity and that increased DES1 levels-found in a third of HER2+ breast cancers-are associated with worse survival outcomes. Taken together, our findings reveal a novel pro-tumor role for DES1 as a transducer of HER2-driven glucose metabolic signals and provide evidence that targeting DES1 is an effective approach for overcoming AIS. Results further suggest that DES1 may have utility as a biomarker of aggressive and metastasis-prone HER2+ breast cancer.

The Healthy Eating and Living Against Noncommunicable Diseases Study: An Innovative Family-Based Intervention.

OBJECTIVE: Inadequate nutrition literacy within families is a barrier for healthy dietary choices and influences chronic disease risk. This pilot study examined the feasibility of providing an in-person nutrition intervention for families at high risk of developing prediabetes or type 2 diabetes and cardiovascular risk-factors. METHODS: Eligible families had at least one member with a non-communicable disease (NCD) or metabolic risk factor, fluency in English, willingness to attend all three educational sessions and complete questionnaires as a family unit. Sessions included didactic and experiential activities on food label reading, portion sizing, physical activity and modifiable lifestyle factors to reduce NCD risk. Demographics and fruit and vegetable screeners were collected from all participants at baseline and after completion of sessions. Families participated in focus groups to evaluate the program. RESULTS: Twelve families (n=35;17 adults;18 children) were recruited from New York City. Participants self-identified as Asian, Hispanic or Black. Adults had a mean age of 40y, BMI of 32.29kg/m2, household income of $35,000-$49,000y, and 13 of 17 adult participants had college degrees. Children ranged from 1-17y. Based on focus group feedback, three sessions were acceptable, families reported enjoying interactive activities and group learning and requested child-friendly activities. They reported improved knowledge of food labels, strategies for grocery shopping, portion-sizing, and increased awareness of the links between diet quality and NCDs. CONCLUSIONS AND IMPLICATIONS: The study met recruitment goals within 4 months. The educational intervention was acceptable and may be scaled-up for future studies on NCD prevention, particularly prediabetes and type 2 diabetes.

ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation.

Neutral sphingomyelinase-2 (nSMase2) is a key ceramide-producing enzyme in cellular stress responses. While many posttranslational regulators of nSMase2 are known, emerging evidence suggests a more protracted regulation of nSMase2 at the transcriptional level. Previously, we reported that nSMase2 is induced by all-trans retinoic acid (ATRA) in MCF7 cells and implicated nSMase2 in ATRA-induced growth arrest. Here, we further investigated how ATRA regulates nSMase2. We find that ATRA regulates nSMase2 transcriptionally through the retinoic acid receptor-α, but this is independent of previously identified transcriptional regulators of nSMase2 (Sp1, Sp3, Runx2) and is not through increased promoter activity. Epigenetically, the nSMase2 gene is not repressively methylated in MCF7 cells. However, inhibition of histone deacetylases (HDACs) with trichostatin A (TSA) induced nSMase2 comparably to ATRA; furthermore, combined ATRA and TSA treatment was not additive, suggesting ATRA regulates nSMase2 through direct modulation of histone acetylation. Confirming this, the histone acetyltransferases CREB-binding protein and p300 were required for ATRA induction of nSMase2. Finally, use of class-specific HDAC inhibitors suggested that HDAC4 and/or HDAC5 are negative regulators of nSMase2 expression. Collectively, these results identify a novel pathway of nSMase2 regulation and suggest that physiological or pharmacological modulation of histone acetylation can directly affect nSMase2 levels.