Summary In a genome-wide survey on somatic copy number alterations (SCNAs) of long non-coding RNA (lncRNA) in 2,394 tumor specimens from 12 cancer types, we found that about 21.8% of lncRNA genes were located in regions with focal SCNAs. By integrating bioinformatics analyses of lncRNA SCNAs and expression with functional screening assays, we identified an oncogene, Focally Amplified lncRNA on Chromosome 1 (FAL1), whose copy number and expression are correlated with outcomes in ovarian cancer. FAL1 associates with the epigenetic repressor BMI1 and regulates its stability in order to modulate the transcription of a number of genes including CDKN1A. The oncogenic activity of FAL1 is partially attributable to its repression of p21. FAL1-specific siRNAs significantly inhibit tumor growth in vivo.

Amyloid-␤ (A␤) peptides, consisting mainly of 40 and 42 aa (A␤40 and A␤42, respectively), are metabolites of the amyloid precursor protein and are believed to be major pathological determinants of Alzheimer's disease. The proteolytic cleavages that form the A␤ N and C termini are catalyzed by ␤-secretase and ␥-secretase, respectively. Here we demonstrate that ␥-secretase generation of A␤ in an N2a cell-free system is ATP dependent. In addition, the Abl kinase inhibitor imatinib mesylate (Gleevec, or STI571), which targets the ATP-binding site of Abl and several other tyrosine kinases, potently reduces A␤ production in the N2a cell-free system and in intact N2a cells. Both STI571 and a related compound, inhibitor 2, also reduce A␤ production in rat primary neuronal cultures and in vivo in guinea pig brain. STI571 does not inhibit the ␥-secretase-catalyzed S3 cleavage of Notch-1. Furthermore, production of A␤ and its inhibition by STI571 were demonstrated to occur to similar extents in both Abl ؊/؊ and WT mouse fibroblasts, indicating that the effect of STI571 on A␤ production does not involve Abl kinase. The efficacy of STI571 in reducing A␤ without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer's disease.

Despite the high initial response rates to PARP inhibitors (PARPi) in BRCA-mutated epithelial ovarian cancers (EOC), PARPi resistance remains a major challenge. Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N 6 -methyladenosine (m 6 A) is the most abundant chemical modification of mRNA, yet the role of m 6 A modification in PARPi resistance has not previously been explored. Here, we show that m 6 A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/b-catenin pathway in BRCA-mutated EOC cells. Global m 6 A profile revealed a significant increase in m 6 A modification in FZD10 mRNA, which correlated with increased FZD10 mRNA stability and an upregulation of the Wnt/b-catenin pathway. Depletion of FZD10 or inhibition of the Wnt/b-catenin sensitizes resistant cells to PARPi. Mechanistically, downregulation of m 6 A demethylases FTO and ALKBH5 was suffi-cient to increase FZD10 mRNA m 6 A modification and reduce PARPi sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of PARP and Wnt/b-catenin showed synergistic suppression of PARPi-resistant cells in vitro and in vivo in a xenograft EOC mouse model. Overall, our results show that m 6 A contributes to PARPi resistance in BRCA-deficient EOC cells by upregulating the Wnt/b-catenin pathway via stabilization of FZD10. They also suggest that inhibition of the Wnt/b-catenin pathway represents a potential strategy to overcome PARPi resistance.Significance: These findings elucidate a novel regulatory mechanism of PARPi resistance in EOC by showing that m 6 A modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/b-catenin pathway.

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinumbased chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescenceassociated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both in vitro and in vivo. Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOCbearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescenceassociated CSCs.Significance: This study highlights the importance of NAMPTmediated NAD þ biosynthesis in the production of cisplatininduced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.

Highlights d EZH2 inhibitor sensitizes CARM1-high EOC cells to PARP inhibitor d EZH2 inhibitor upregulates MAD2L2 and NHEJ activity in CARM1-high EOC cells d EZH2 and PARP inhibitor combination causes mitotic catastrophe d EZH2 and PARP inhibitors are synergistic in suppressing CARM1-high EOCs in vivo