Lysine-specific demethylase 1 (LSD1) exerts pathway-specific activity in animal development and has been linked to several high-risk cancers. Here, we report that LSD1 is an integral component of the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex. Transcriptional target analysis revealed that the LSD1/NuRD complexes regulate several cellular signaling pathways including TGFbeta1 signaling pathway that are critically involved in cell proliferation, survival, and epithelial-to-mesenchymal transition. We demonstrated that LSD1 inhibits the invasion of breast cancer cells in vitro and suppresses breast cancer metastatic potential in vivo. We found that LSD1 is downregulated in breast carcinomas and that its level of expression is negatively correlated with that of TGFbeta1. Our data provide a molecular basis for the interplay of histone demethylation and deacetylation in chromatin remodeling. By enlisting LSD1, the NuRD complex expands its chromatin remodeling capacity to include ATPase, histone deacetylase, and histone demethylase.

Nonsyndromic cleft lip with or without a cleft palate (NSCL/P) is among the most common human congenital birth defects and imposes a substantial physical and financial burden on affected individuals. Here, we conduct a case-control-based GWAS followed by two rounds of replication; we include six independent cohorts from China to elucidate the genetic architecture of NSCL/P in Chinese populations. Using this combined analysis, we identify a new locus at 16p13.3 associated with NSCL/P: rs8049367 between CREBBP and ADCY9 (odds ratio ¼ 0.74, P ¼ 8.98 Â 10 À 12 ). We confirm that the reported loci at 1q32.2, 10q25.3, 17p13.1 and 20q12 are also involved in NSCL/P development in Chinese populations. Our results provide additional evidence that the rs2235371-related haplotype at 1q32.2 could play a more important role than the previously identified causal variant rs642961 in Chinese populations. These findings provide information on the genetic basis and mechanisms of NSCL/P.

Purpose: Recent studies have suggested that microRNA biomarkers could be useful for stratifying lung cancer subtypes, but microRNA signatures varied between different populations. Squamous cell carcinoma (SCC) is one major subtype of lung cancer that urgently needs biomarkers to aid patient management. Here, we undertook the first comprehensive investigation on microRNA in Chinese SCC patients.Experimental Design: MicroRNA expression was measured in cancerous and noncancerous tissue pairs strictly collected from Chinese SCC patients (stages I-III), who had not been treated with chemotherapy or radiotherapy prior to surgery. The molecular targets of proposed microRNA were further examined.Results: We identified a 5-microRNA classifier (hsa-miR-210, hsa-miR-182, hsa-miR-486-5p, hsamiR-30a, and hsa-miR-140-3p) that could distinguish SCC from normal lung tissues. The classifier had an accuracy of 94.1% in a training cohort (34 patients) and 96.2% in a test cohort (26 patients). We also showed that high expression of hsa-miR-31 was associated with poor survival in these 60 SCC patients by Kaplan-Meier analysis (P ¼ 0.007), by univariate Cox analysis (P ¼ 0.011), and by multivariate Cox analysis (P ¼ 0.011). This association was independently validated in a separate cohort of 88 SCC patients (P ¼ 0.008, 0.011, and 0.003 in Kaplan-Meier analysis, univariate Cox analysis, and multivariate Cox analysis, respectively). We then determined that the tumor suppressor DICER1 is a target of hsa-miR-31. Expression of hsa-miR-31 in a human lung cancer cell line repressed DICER1 activity but not PPP2R2A or LATS2.Conclusions: Our results identified a new diagnostic microRNA classifier for SCC among Chinese patients and a new prognostic biomarker, hsa-miR-31. Clin Cancer Res; 17(21); 6802-11. Ó2011 AACR.