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Wang, Lu

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Wang

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Lu

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Wang, Lu
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    The ATPase Module of Mammalian SWI/SNF Family Complexes Mediates Subcomplex Identity and Catalytic Activity–independent Genomic Targeting
    (Springer Science and Business Media LLC, 2019-03-11) Mashtalir, Nazar; Wang, Lu; Kadoch, Cigall; Pan, Joshua; McKenzie, Zachary; D’Avino, Andrew; Lareau, Caleb; St. Pierre, Roodolph; Shilatifard, Ali
    Perturbations to mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes have been widely implicated as driving events in cancer1. One such perturbation is the dual loss of the SMARCA4 and SMARCA2 ATPase subunits in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)2-5, SMARCA4-deficient thoracic sarcomas6 and dedifferentiated endometrial carcinomas7. However, the consequences of dual ATPase subunit loss on mSWI/SNF complex subunit composition, chromatin targeting, DNA accessibility and gene expression remain unknown. Here we identify an ATPase module of subunits that is required for functional specification of BAF and PBAF subcomplexes. Using SMARCA4/2 ATPase mutant variants, we define the catalytic activity -dependent and -independent contributions of the ATPase module to the targeting of BAF and PBAF complexes genome-wide. Finally, by linking distinct mSWI/SNF complex target sites to tumor-suppressive gene expression programs, we clarify the transcriptional consequences of SMARCA4/2 dual loss in SCCOHT.
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    Synthesis-free PET imaging of brown adipose tissue and TSPO via combination of disulfiram and 64CuCl2
    (Nature Publishing Group UK, 2017) Yang, Jing; Yang, Jian; Wang, Lu; Moore, Anna; Liang, Huan; Ran, Chongzhao
    PET imaging is a widely applicable but a very expensive technology. On-site synthesis is one important contributor to the high cost. In this report, we demonstrated the feasibility of a synthesis-free method for PET imaging of brown adipose tissue (BAT) and translocator protein 18 kDa (TSPO) via a combination of disulfiram, an FDA approved drug for alcoholism, and 64CuCl2 (termed 64Cu-Dis). In this method, a step-wise injection protocol of 64CuCl2 and disulfiram was used to accomplish the purpose of synthesis-free. Specifically, disulfiram, an inactive 64Cu ligand, was first injected to allow it to metabolize into diethyldithiocarbamate (DDC), a strong 64Cu ligand, which can chelate 64CuCl2 from the following injection to form the actual PET tracer in situ. Our blocking studies, western blot, and tissue histological imaging suggested that the observed BAT contrast was due to 64Cu-Dis binding to TSPO, which was further confirmed as a specific biomarker for BAT imaging using [18F]-F-DPA, a TSPO-specific PET tracer. Our studies, for the first time, demonstrated that TSPO could serve as a potential imaging biomarker for BAT. We believe that our strategy could be extended to other targets while significantly reducing the cost of PET imaging.
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    Publication
    Association between Vitamin D Genetic Risk Score and Cancer Risk in a Large Cohort of U.S. Women
    (MDPI, 2018) Chandler, Paulette; Tobias, Deirdre; Wang, Lu; Smith-Warner, Stephanie; Chasman, Daniel; Rose, Lynda; Giovannucci, Edward; Buring, Julie; Ridker, Paul; Cook, Nancy; Manson, JoAnn; Sesso, Howard
    Some observational studies suggest an inverse association between circulating 25-hydroxyvitamin D (25OHD) and cancer incidence and mortality. We conducted a Mendelian randomization analysis of the relationship between a vitamin D genetic risk score (GRS, range 0–10), comprised of five single nucleotide polymorphisms (SNPs) of vitamin D status in the DHCR7, CYP2R1 and GC genes and cancer risk among women. Analysis was performed in the Women’s Genome Health Study (WGHS), including 23,294 women of European ancestry who were cancer-free at baseline and followed for 20 years for incident cancer. In a subgroup of 1782 WGHS participants with 25OHD measures at baseline, the GRS was associated with circulating 25OHD mean (SD) = 67.8 (26.1) nmol/L, 56.9 (18.7) nmol/L in the lowest versus 73.2 (27.9) nmol/L in the highest quintile of the GRS (p trend < 0.0001 across quintiles). However, in age-adjusted Cox proportional hazards models, higher GRS (reflecting higher 25OHD levels) was not associated (cases; Hazard Ratio (HR) (95% Confidence Interval (CI)), p-value) with incident total cancer: (n = 3985; 1.01 (1.00–1.03), p = 0.17), breast (n = 1560; 1.02 (0.99–1.05), p = 0.21), colorectal (n = 329; 1.06 (1.00–1.13), p = 0.07), lung (n = 330; 1.00 (0.94–1.06), p = 0.89) or total cancer death (n = 770; 1.00 (0.96–1.04), p = 0.90). Results were similar in fully-adjusted models. A GRS for higher circulating 25OHD was not associated with cancer incidence or mortality.