Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.

The objective of the present study was to investigate the association between gene E-cadherin single nucleotide polymorphisms (SNPs) and risk of developing endometriosis in Indian women and to evaluate the role of E-cadherin expression in the pathophysiology of endometriosis. A genetic association study was conducted in 715 endometriosis cases and 500 controls of Indian origin. We genotyped −160 C/A, +54 C/T and −347 G/GA SNPs of gene E-cadherin by PCR-sequencing and PCR-restriction fragment length polymorphism techniques. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D′) for pair-wise linkage disequilibrium (LD) were assessed by Haploview Software. In addition, to better understand genetic contributions to the pathophysiology of endometriosis, the expression pattern of E-cadherin in the endometrium of women with and without endometriosis was analyzed by western blot and immunohistochemical analysis. The frequencies of −347GA/GA (P = 0.026) and −160A/A (P = 0.0019) genotypes and −347G/−160A/+54C (P = 0.007) and −347GA/−160A/+54C (P < 0.0001) haplotypes were significantly different between patients and controls. Strong LD was observed between −347G/GA and −160C/A loci (D′ = 0.64) when compared with −347G/GA and +54C/T (D′ = 0.585) or −160C/A and +54C/T (D′ = 0.05) loci in cases. Furthermore, increased membranous E-cadherin expression was observed in cases than in controls. The expression seems to be genotype dependent. In conclusion, the E-cadherin −347GA/GA and −160A/A genotypes and −347GA/−160A/+54C and −347G/−160A/+54C haplotypes may jointly modify the risk of endometriosis in Indian women. In addition, the differential expression of E-cadherin may play an important role in pathogenesis of endometriosis.

Aims: Release of large amounts of free heme into circulation, overproduction of reactive oxygen species (ROS), and activation of toll-like receptor-4-dependent responses are considered critical for the ability of heme to promote oxidative stress and to initiate proinflammatory responses, posing a serious threat to the body. A deep understanding of the consequences of heme overload on the regulation of cellular and systemic iron homeostasis is, however, still lacking. Results: The effects of heme on iron metabolism were studied in primary macrophages and in mouse models of acute and chronic hemolysis. We demonstrated that hemolysis was associated with a significant depletion of intracellular iron levels and increased expression of the sole iron exporter protein, ferroportin. The pathophysiological relevance of this mechanism was further demonstrated in sickle cell anemia mice, which, despite chronic hemolysis, maintained high ferroportin expression and increased iron export. We identified a redox active iron species and superoxide as regulators for ferroportin induction by heme. Scavenging the ROS production, by use of a pharmacological antioxidant N-acetylcysteine, prevented ferroportin induction and normalized intracellular iron levels in macrophages and in experimentally induced hemolysis in mice. Innovation: Our data propose that scavenging ROS levels may be a novel therapeutic strategy to balance intracellular iron levels and systemic iron influx in conditions associated with heme overload. Conclusion: This study identifies that the pro-oxidant, and not the proinflammatory, actions of heme profoundly impact on iron homeostasis by critically regulating the expression of ferroportin and iron export in hemolytic conditions. Antioxid. Redox Signal. 29, 484–499.

In this article, we report the development and preclinical validation of combinatorial therapy for treatment of cancers using RNA interference (RNAi). RNAi technology is an attractive approach to silence genes responsible for disease onset and progression. Currently, the critical challenge facing the clinical success of RNAi technology is in the difficulty of delivery of RNAi inducers, due to low transfection efficiency, difficulties of integration into host DNA and unstable expression. Using the macromolecule polyglycidal methacrylate (PGMA) as a platform to graft multiple polyethyleneimine (PEI) chains, we demonstrate effective delivery of small oligos (anti-miRs and mimics) and larger DNAs (encoding shRNAs) in a wide variety of cancer cell lines by successful silencing/activation of their respective target genes. Furthermore, the effectiveness of this therapy was validated for in vivo tumor suppression using two transgenic mouse models; first, tumor growth arrest and increased animal survival was seen in mice bearing Brca2/p53-mutant mammary tumors following daily intratumoral treatment with nanoparticles conjugated to c-Myc shRNA. Second, oral delivery of the conjugate to an Apc-deficient crypt progenitor colon cancer model increased animal survival and returned intestinal tissue to a non–wnt-deregulated state. This study demonstrates, through careful design of nonviral nanoparticles and appropriate selection of therapeutic gene targets, that RNAi technology can be made an affordable and amenable therapy for cancer. Mol Cancer Ther; 14(5); 1259–69. ©2015 AACR.

One of the most prevalent genetic iron overload disorders in Caucasians is caused by mutations in the HFE gene. Both HFE patients and Hfe‐mouse models develop a progressive accumulation of iron in the parenchymal cells of various tissues, eventually resulting in liver cirrhosis, hepatocellular carcinoma, cardiomyopathies, hypogonadism, and other pathologies. Clinical data and preclinical models have brought considerable attention to the correlation between iron overload and the development of osteoporosis in HFE/Hfe hemochromatosis. Our study critically challenges this concept. We show that systemic iron overload, at the degree present in Hfe^−/− mice, does not associate with the microarchitecture impairment of long bones, thus excluding a negative effect of iron overload on bone integrity. We further reveal that Hfe actions in osteoblasts and osteoclasts are dispensable for the maintenance of bone and iron homeostasis in mice under steady‐state conditions. We conclude that, despite systemic iron overload, Hfe^−/− mice present normal physiological bone homeostasis. © 2019 The Authors. JBMR Plus in published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.