TET1 regulates gene expression by demethylating their regulatory sequences through the conversion of 5-methylcytosine to 5-hyroxymethylcytosine. TET1 plays important roles in tissue homeostasis. In breast cancer, TET1 was shown to play controversial roles. Moreover, TET1 has at least two isoforms (long and short) that have distinct expression pattern and apparently different functions in tissue development and disease including breast cancer. We hypothesized that TET1 isoforms have different expression patterns, localization and regulation in different types of breast cancer. To prove our hypothesis, we studied the expression of TET1 isoforms in basal and luminal breast cancer cell lines, as well as in basal and luminal breast cancer animal models. We also studied the effect of different hormones on the expression of the two isoforms. Moreover, we assessed the distribution of the isoforms between the cytoplasm and nucleus. Finally, we overexpressed the full length in a breast cancer cell line and tested its effect on cancer cell behavior. In this study, we demonstrate that while Estrogen and GnRH downregulate the expression of long TET1, they lead to upregulation of short TET1 expression. In addition, we uncovered that luminal cells show higher expression level of the long isoform. We also show that while all TET1 isoforms are almost depleted in a basal breast cancer animal model, the expression of the short isoform is induced in luminal breast cancer model. The short form is expressed mainly in the cytoplasm while the long isoform is expressed mainly in the nucleus. Finally, we show that long TET1 overexpression suppresses cell oncogenic phenotypes. In conclusion, our data suggest that TET1 isoforms have distinct expression pattern, localization and regulation in breast cancer and that long TET1 suppresses oncogenic phenotypes, and that further studies are necessary to elucidate the functional roles of different TET1 isoforms in breast cancer.

Cancer is a leading cause of death worldwide, and most of the currently available drugs for cancer treatment have limited potential. Natural products and their relatives continue to represent a very high percentage of the drugs used for cancer treatment. Curcumin is one of several natural drugs that has recently attracted much attention due to its putative cancer-preventive and anticancer properties. As well, Nitric Oxide (NO) holds a great potential for NO-based treatments for a wide variety of diseases. Here, for the first time, we tested the anti-cancer activities of an NO–Curcumin hybrid, hypothesizing that by joining the effects of curcumin and NO in one compound, the hybrid compound would be more potent than curcumin alone in treating colon cancer. To compare the anti-cancer activities of curcumin and NO–curcumin, we treated different colon cancer cell lines with either curcumin or NO–curcumin and tested their effects on cell proliferation and death. Our results show that NO–curcumin is more effective in reducing cell proliferation and increasing cell death when compared to curcumin. In addition, NO–curcumin has a lower IC50 compared to curcumin. Altogether, our results demonstrate for the first time that an NO–curcumin hybrid has more potent anti-cancer activity compared to curcumin alone, making it a potential future treatment for cancer and perhaps other diseases.

Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder, which is characterized primarily by an inability to perceive physical pain from birth, resulting in the accumulation of bruising, inflammation and fractures that affect patient's life expectancy. In Palestine, because of high rate of consanguinity, this rare disease seems to have higher frequency than in other communities. However, there were no systematic studies to address the genetic factors that cause CIP in the Palestinian community. In this study, we genotyped members of five Palestinian CIP-affected families using Sanger and Whole exome sequencing approaches. Our results confirmed the presence of the founder mutation c.1931-ins- T in the NTRK1 gene of Palestinian Bedouin CIPA patients. This mutation was found in three out of the five participating families. In addition, in one CIPA family, we found the missense mutation (c.2170 G > A (G724 S) in exon 16 of NTRK1 gene. Finally, a novel nonsense mutation (c.901A > T, K301*) was detected in exon 7 of the SCN9A gene in CIP without anhidrosis family. In conclusion our study revealed three mutations that caused CIP, and CIPA in Palestinian community which would help in improving the diagnostic and genetic counseling process. And help in building a diagnostic and follow up protocol for the affected individuals, since early diagnosis and medical care interference could prevent a lot of unpleasant complication of CIP, and CIPA patients.

Background Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder characterized primarily by an inability to perceive physical pain from birth, resulting in the accumulation of bruising, inflammation, and fractures that affect patient’s life expectancy. CIP has different forms including CIP and CIPA. CIP with Anhidrosis (CIPA) is the most common type of CIP, which is caused mainly by mutations in NTRK1 and NGF genes, and is characterized by mental retardation and the inability to sweat (Anhidrosis). Because of high consanguinity rates in Palestine, this rare disease appears to have a higher frequency than in other communities. However, there were no systematic studies to address the genetic factors that cause CIP in the Palestinian community. Methods In our study, we used Sanger and Whole exome sequencing to genotype members of five CIP-affected Palestinian families. Results Our results confirm the presence of the founder c.1860-1861insT mutation in the NTRK1 gene of Palestinian Bedouin CIPA patients. Furthermore, one CIPA family carried a missense c.2170 G > A (G724 S) mutation in exon 16 of the NTRK1 gene. Finally, a novel nonsense c.901 A > T mutation (K301*) was detected in exon 7 of the SCN9A gene in CIP without anhidrosis family. Conclusions Our study revealed three mutations that cause CIP and CIPA in the Palestinian community, which can help in improving the process of diagnosis and genetic counseling and establishing protocols for the diagnosis and follow-up for the affected individuals. This is especially important given that early diagnosis and medical care interference can prevent unpleasant CIP and CIPA complications.