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Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and non-coding RNA, have been studied for the last two decades. Epigenetic dysregulation is often reported in the development and progression of various cancers. Recently, epigenetic changes in endometrial cancer have also been discussed. In this review, we give the main points of the role of DNA methylation and histone modification in endometrial cancer, the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials.

Endometrial cancer is a ubiquitous gynecological disease with increasing global incidence. Therefore, despite the lack of an established screening technique to date, early diagnosis of endometrial cancer assumes critical importance. This paper presents an artificial-intelligence-based system to detect the regions affected by endometrial cancer automatically from hysteroscopic images. In this study, 177 patients (60 with normal endometrium, 21 with uterine myoma, 60 with endometrial polyp, 15 with atypical endometrial hyperplasia, and 21 with endometrial cancer) with a history of hysteroscopy were recruited. Machine-learning techniques based on three popular deep neural network models were employed, and a continuity-analysis method was developed to enhance the accuracy of cancer diagnosis. Finally, we investigated if the accuracy could be improved by combining all the trained models. The results reveal that the diagnosis accuracy was approximately 80% (78.91–80.93%) when using the standard method, and it increased to 89% (83.94–89.13%) and exceeded 90% (i.e., 90.29%) when employing the proposed continuity analysis and combining the three neural networks, respectively. The corresponding sensitivity and specificity equaled 91.66% and 89.36%, respectively. These findings demonstrate the proposed method to be sufficient to facilitate timely diagnosis of endometrial cancer in the near future.

Chemotherapy plays an important role in the treatment of patients with gynecological cancers. Delivering anticancer drugs effectively to tumor cells with just few side effects is key in cancer treatment. Lipid bubbles (LB) are compounds that increase the vascular permeability of the tumor under diagnostic ultrasound (US) exposure and enable the effective transport of drugs to tumor cells. The aim of our study was to establish a novel drug delivery technique for chemotherapy and to identify the most effective anticancer drugs for the bubble US‐mediated drug delivery system (BUS‐DDS) in gynecological cancer treatments. We constructed xenograft models using cervical cancer (HeLa) and uterine endometrial cancer (HEC1B) cell lines. Lipid bubbles were injected i.v., combined with either cisplatin (CDDP), pegylated liposomal doxorubicin (PLD), or bevacizumab, and US was applied to the tumor. We compared the enhanced chemotherapeutic effects of these drugs and determined the optimal drugs for BUS‐DDS. Tumor volume reduction of HeLa and HEC1B xenografts following cisplatin treatment was significantly enhanced by BUS‐DDS. Both CDDP and PLD significantly enhanced the antitumor effects of BUS‐DDS in HeLa tumors; however, volume reduction by BUS‐DDS was insignificant when combined with bevacizumab, a humanized anti‐vascular endothelial growth factor mAb. The BUS‐DDS did not cause any severe adverse events and significantly enhanced the antitumor effects of cytotoxic drugs. The effects of bevacizumab, which were not as dose‐dependent as those of the two drugs used prior, were minimal. Our data suggest that BUS‐DDS technology might help achieve “reinforced targeting” in the treatment of gynecological cancers. In vivo application of the bubble ultrasound (US)‐mediated drug delivery system in mouse xenograft tumors. Anticancer drugs were injected with lipid bubbles into the tail vein. The US probe was placed on the tumor and US exposure was simultaneously initiated.

Background Uterine leiomyosarcoma (uLMS) has a poor prognosis owing to its resistance to chemotherapy. Therefore, novel therapeutic targets for uLMS should be identified. Suppressor license of variegation 3–9 homolog 2 (SUV39H2) is a histone methyltransferase that promotes the repair of double-strand DNA breaks by recruiting phosphorylated H2AX (γH2AX). In this study, we investigated the potential therapeutic targets of SUV39H2 in uLMS and the mechanism of synthetic lethality between PARP inhibitors and the SUV39H2 inhibitor OTS186935. Methods First, we analyzed the mRNA and protein expression of SUV39H2 in the clinical tissues of uLMS, normal myometrium, and leiomyomas using real-time polymerase chain reaction and immunohistochemistry, respectively. Next, we conducted drug sensitivity assays for OTS186935 alone and in combination with olaparib, a poly (ADP-ribose) polymerase inhibitor, using the uLMS cell lines SK-LMS-1 and SK-UT-1. We performed western blotting, immunofluorescence, and chromatin immunoprecipitation sequencing (ChIP-seq) to investigate γH2AX following OTS186935 treatment in addition to in vivo experiments using nude mice with subcutaneously implanted uLMS. Results SUV39H2 expression in uLMS was significantly higher than that in the normal myometrium and leiomyomas. OTS186935 decreased the viability of both cell lines, and its combination with olaparib resulted in synthetic lethality in SK-UT-1 cells (combination index = 0.88). After treatment with OTS186935, γH2AX accumulation decreased. ChIP-seq also showed downregulation of γH2AX following OTS186935 treatment. Notably, the combination of OTS186935 and a PARP inhibitor was significantly more effective in vivo. Conclusion OTS186935 inhibited double-strand DNA break repair, as evidenced by γH2AX downregulation by ChIP-seq and other assays. Combining OTS186935 with olaparib demonstrated activity resembling synthetic lethality; however, further validation is required before clinical translation.

The purpose of this study is to clarify the metabolic dependence of ovarian clear cell carcinoma (CCC) by comparing normal tissues and to examine the applicability of fluorescence imaging probe to exploit these metabolic differences. Enhanced glutathione synthesis was supported by the increased uptake of related metabolites and elevated expression levels of genes. Accumulation of intracellular iron and lipid peroxide, induction of cell death by inhibition of the glutathione synthesis pathway indicated that ferroptosis was induced. The activation of γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent imaging probe that recognizes γ-glutamyl transferase, which is essential for the synthesis of glutathione, was investigated in fresh-frozen surgical specimens. gGlu-HMRG detected extremely strong fluorescent signals in the tumor lesions of CCC patients, compared to normal ovaries or endometrium. These results revealed that CCC occurs in the stressful and unique environment of free radical-rich endometrioma, and that glutathione metabolism is enhanced as an adaptation to oxidative stress. Furthermore, a modality that exploits these metabolic differences would be useful for distinguishing between CCC and normal tissues.

Uterine sarcomas have very poor prognoses and are sometimes difficult to distinguish from uterine leiomyomas on preoperative examinations. Herein, we investigated whether deep neural network (DNN) models can improve the accuracy of preoperative MRI-based diagnosis in patients with uterine sarcomas. Fifteen sequences of MRI for patients (uterine sarcoma group: n = 63; uterine leiomyoma: n = 200) were used to train the models. Six radiologists (three specialists, three practitioners) interpreted the same images for validation. The most important individual sequences for diagnosis were axial T2-weighted imaging (T2WI), sagittal T2WI, and diffusion-weighted imaging. These sequences also represented the most accurate combination (accuracy: 91.3%), achieving diagnostic ability comparable to that of specialists (accuracy: 88.3%) and superior to that of practitioners (accuracy: 80.1%). Moreover, radiologists’ diagnostic accuracy improved when provided with DNN results (specialists: 89.6%; practitioners: 92.3%). Our DNN models are valuable to improve diagnostic accuracy, especially in filling the gap of clinical skills between interpreters. This method can be a universal model for the use of deep learning in the diagnostic imaging of rare tumors.

Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multi-omics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq). The expression of PRMT6 in EC was analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6-knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIP-seq of H3K27ac antibodies and RNA-seq. Finally, the downstream targets identified by multi-omics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6-KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIP-seq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNA-seq data demonstrated altered interferon-related pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide-3-kinase regulatory subunit 1, following PRMT6-KD. RT-qPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6-KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.

Homologous recombination (HR) is a major repair pathway of DNA double-strand breaks and is closely related to carcinogenesis. HR deficiency has been established as a therapeutic target. The aim of this study was to elucidate the functions of a novel HR factor, Mediator complex subunit 1 (MED1), and its association with BRCA1. Formation of the MED1/BRCA1 complex was examined by immunoprecipitation and GST-pull down assays. The transcription cofactor role of BRCA1 was evaluated using luciferase assays. The roles of MED1 on DNA damage response and HR were analyzed by immunofluorescence and HR assays. R-loop accumulation was analyzed using immunofluorescence. R-loop-induced DNA damage was analyzed by comet assays. Immunoprecipitation and GST-pull down assays demonstrated that MED1 is a novel binding partner of BRCA1 and binds to the BRCT domain. Luciferase assays showed that MED1 potentiated the transcription ability of BRCT by two-fold. In MED1-depleted cells, recruitment of HR genes, such as RPA and γH2AX, to DNA damage sites was severely impaired. HR assays showed that MED1 knockdown significantly decreased HR activity. R-loop nuclear accumulation and R-loop-induced comet tails were observed in MED1-depleted cells. We conclude that the transcription factor MED1 contributes to the regulation of the HR pathway and R-loop processing.

The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.

Background Wolf-Hirschhorn syndrome candidate gene-1 (WHSC1), a histone methyltransferase, has been found to be upregulated and its expression to be correlated with expression of enhancer of zeste homolog 2 (EZH2) in several cancers. In this study, we evaluated the role of WHSC1 and its therapeutic significance in ovarian clear cell carcinoma (OCCC). Methods First, we analyzed WHSC1 expression by quantitative PCR and immunohistochemistry using 23 clinical OCCC specimens. Second, the involvement of WHSC1 in OCCC cell proliferation was evaluated by MTT assays after siRNA-mediated WHSC1 knockdown. We also performed flow cytometry (FACS) to address the effect of WHSC1 on cell cycle. To examine the functional relationship between EZH2 and WHSC1, we knocked down EZH2 using siRNAs and checked the expression levels of WHSC1 and its histone mark H3K36m2 in OCCC cell lines. Finally, we checked WHSC1 expression after treatment with the selective inhibitor, GSK126. Results Both quantitative PCR and immunohistochemical analysis revealed that WHSC1 was significantly overexpressed in OCCC tissues compared with that in normal ovarian tissues. MTT assay revealed that knockdown of WHSC1 suppressed cell proliferation, and H3K36me2 levels were found to be decreased in immunoblotting. FACS revealed that WHSC1 knockdown affected the cell cycle. We also confirmed that WHSC1 expression was suppressed by EZH2 knockdown or inhibition, indicating that EZH2 is upstream of WHSC1 in OCCC cells . Conclusions WHSC1 overexpression induced cell growth and its expression is, at least in part, regulated by EZH2. Further functional analysis will reveal whether WHSC1 is a promising therapeutic target for OCCC.