Inhibition of cancer cell proliferation by 5-fluoro-2'-deoxycytidine, a DNA methylation inhibitor, through activation of DNA damage response pathway

Abstract Multiple epigenetic changes, including alterations in DNA methylation occur during tumorigenesis. Various inhibitors of DNA methylation have been developed to prevent proliferation of cancer cells. 5-fluoro-2′-deoxycytidine (FCdR) is one such DNA methylation inhibitor, which is currently in phase II clinical trial. To investigate the molecular mechanism/s by which FCdR might mediate repression of tumor cell proliferation, we analyzed the toxicity of FCdR in various cell lines established from different sarcomas. We found HCT116, a colon cancer cell line, is much more sensitive to FCdR compared to others. FCdR treatment inhibited HCT116 cells at G2/M check point and up-regulated expression of multiple cancer-related genes, which could be due to its inhibitory activity towards DNA methylation. Furthermore, we found that FCdR activates DNA damage response pathway. Using an inhibitor for ATM and ATR kinases activity, which are required for amplifying the DNA damage repair signal, we show that FCdR induced inhibition of HCT116 cells at G2/M is mediated through activation of DNA damage response pathway.</jats:p

Global histone modification profiling reveals the epigenomic dynamics during malignant transformation in a four-stage breast cancer model

BACKGROUND: Epigenetic regulation has emerged to be the critical steps for tumorigenesis and metastasis. Multiple histone methyltransferase and demethylase have been implicated as tumor suppressors or oncogenes recently. But the key epigenomic events in cancer cell transformation still remain poorly understood. METHODS: A breast cancer transformation model was established via stably expressing three oncogenes in primary breast epithelial cells. Chromatin immunoprecipitation followed by the next-generation sequencing of histone methylations was performed to determine epigenetic events during transformation. Western blot, quantitative RT-PCR, and immunostaining were used to determine gene expression in cells and tissues. RESULTS: Histones H3K9me2 and me3, two repressive marks of transcription, decrease in in vitro breast cancer cell model and in vivo clinical tissues. A survey of enzymes related with H3K9 methylation indicated that KDM3A/JMJD1A, a demethylase for H3K9me1 and me2, gradually increases during cancer transformation and is elevated in patient tissues. KDM3A/JMJD1A deficiency impairs the growth of tumors in nude mice and transformed cell lines. Genome-wide ChIP-seq analysis reveals that the boundaries of decreased H3K9me2 large organized chromatin K9 modifications (LOCKs) are enriched with cancer-related genes, such as MYC and PAX3. Further studies show that KDM3A/JMJD1A directly binds to these oncogenes and regulates their transcription by removing H3K9me2 mark. CONCLUSIONS: Our study demonstrates reduction of histones H3K9 me2 and me3, and elevation of KDM3A/JMJD1A as important events for breast cancer, and illustrates the dynamic epigenomic mechanisms during breast cancer transformation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-016-0201-x) contains supplementary material, which is available to authorized users

Torsion of ovarian endometrioma in pregnancy: a case report and review of the literature

Adnexal torsion induced by an endometrioma has seldom been reported. Because of its rarity and its complexity in respect of fetal health during pregnancy, the diagnosis and treatment is challenging. We report a 25-year-old primigravida in the eighth week of gestation presenting with acute onset lower abdominal pain. A pelvic ultrasonography showed an intrauterine single viable embryo with a right ovarian cyst measuring 6 × 6 cm in diameter. Exploratory laparotomy revealed torsion of the right adnexa by 360°. After a right adnexectomy was performed, the patient proceeded to full-term pregnancy. Adnexal torsion is defined as rotation of &gt; 45° in the long axis of the adnexae. Its occurrence during gestation is reported as 2%, accounting for 2.7% of surgical emergencies in pregnant women. Most cases are caused by dermoid and functional ovarian cysts. Because of the rarity of torsion induced by an endometrioma, the diagnosis and treatment are challenging. In poor-resource conditions, a diagnostic laparoscopy (or laparotomy) remains a logical method of diagnosis, offering simultaneous therapeutic options. </jats:p