303 research outputs found
Epigenetic Targeting of Aberrant Transcriptional Modulation in Pancreatic Cancer
No full textWhile the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and Forkhead Box A1 (FOXA1), rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner
Abstract 2922: The utility of BET inhibition in the sensitization and re-sensitization of pancreatic cancer cells to paclitaxel
No full textAbstract While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. As late diagnosis and resistance to conventional therapies are major contributors to high mortality rates, novel treatment options are needed to improve the prognosis of pancreatic cancer patients. Recent findings showed that inhibition of the Bromodomain and Extraterminal Domain (BET) family of epigenetic reader proteins is effective, both alone and in combination with conventional chemotherapy, in decreasing pancreatic tumor growth in patient-derived xenografts. Thus, we aim to evaluate the potential role of and mechanisms of action of BET inhibitors (BETi) as an adjuvant therapy option in pancreatic ductal adenocarcinoma. We established L3.6 pancreatic cells that are resistant to paclitaxel by maintaining them in incrementally higher concentrations for 3 months. Paclitaxel-resistant cells showed a half maximal inhibitory concentration (IC50) 100-fold higher than that of parental cells. Intriguingly, we report that low, non-cytostatic concentrations of the BETi, JQ1, not only sensitized cells to paclitaxel, but also induced significant re-sensitization of chemoresistant cells. In order to elucidate the mechanism by which BETi induces chemo-sensitization, we investigated the differential gene expression profiles of resistant and sensitive cells. Thereby, we uncovered that BETi reverses the regulation of transcriptionally-activated genes in resistant cells. Interestingly, these genes showed a major tendency to gain BRD4 at putative enhancer regions. We anticipate that enhancer RNAs (eRNAs) transcribed at these particular enhancers may provide us with novel biomarkers which can be used to predict chemotherapeutic resistance and the possibility of re-sensitization by BETi. In conclusion, we provide evidence that BETi can potentially be used as adjuvant agents in pancreatic cancer. However, approaches may likely be largely independent of their anti-proliferative effects that require higher concentrations and possibly lead to intolerable adverse effects, but rather to their transcriptional regulatory functions that attenuate the activated programs in chemoresistant cancers. Citation Format: Feda H. Hamdan, Ana P. Kutschat, Madhobi Sen, Xin Wang, Steven A. Johnsen. The utility of BET inhibition in the sensitization and re-sensitization of pancreatic cancer cells to paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2922
Abstract 3936: Bromodomain testis-specific protein BRDT is expressed in a subset of esophageal squamous cell carcinomas and controls expression of differentiation-associated genes
No full textAbstract Esophageal cancer is one of the most malignant cancers, ranking as the sixth leading cause of cancer-related deaths worldwide. The poor survival rate and prognosis highlight the limitations in the biological understanding of esophageal cancer and the urgent need for identification of novel targeted molecular therapies. Recently, large scale genomic analyses have revealed the extensive alternations of epigenetic regulators which may be used as a basis for developing new “epigenetic drugs “. BRDT, bromodomain testis-specific protein, is a member of the bromodomain and extra-terminal (BET) family of epigenetic reader proteins. BET proteins can regulate gene expression by recognizing acetylated lysines, thus playing important roles in both normal development and disease progression. Inhibition of BET proteins has emerged as a potential therapy for many types of cancer. In normal human tissues, unlike the other members of BET family, BRDT is exclusively highly expressed in testes where it drives the meiotic and post-meiotic gene expression to promote spermatogenesis. We have identified BRDT to be expressed in over 20% of esophageal squamous cell carcinoma (ESCC), a predominant subtype of esophageal cancer. Knockdown of BRDT does not affect cell proliferation, but leads to alterations in the expression of differentiation markers. In addition, RNA-seq following BRDT knockdown also supports a role of BRDT in cell differentiation. Depletion of BRDT does not alter the cellular response to BET inhibition. Surprisingly, we also identified BRDT transcripts encoding two truncated isoforms lacking the first bromodomain, which could potentially alter its epigenetic reader function. The genome occupancy profile of BRDT showed a significant enrichment at transcription start site (TSS), which is distinct from BRD4. It also showed potential interactions between BRDT and E2F family and SMAD family. Together, we showed that BRDT is overexpressed in ESCC cell lines and may influence ESCC development or progression in a subset of tumors by regulating cell differentiation-associated genes. Citation Format: Xin Wang, Feda H. Hamdan, Madhobi Sen, Ana P. Kutschat, Steven A. Johnsen. Bromodomain testis-specific protein BRDT is expressed in a subset of esophageal squamous cell carcinomas and controls expression of differentiation-associated genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3936
DeltaNp63-dependent super enhancers define molecular identity in pancreatic cancer by an interconnected transcription factor network
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Abstract 1472: The role of the BAF complex in Wnt signaling-mediated transcriptional regulation in colorectal cancer
No full textAbstract Recent genome- and exome-wide sequencing studies have revealed a close association between the epigenome and the pathogenesis of cancer. Not only were chromatin regulators found to be commonly mutated in a wide range of cancers, but a class of these regulators, the ATP-dependent chromatin remodelers, especially subunits of the mammalian BAF complex, were among the most frequently mutated group of genes across cancer types, mutated in over 20% of cancers. Among these subunits, loss of function mutations in ARID1A (AT-rich interactive domain-containing protein 1A) are most frequent across cancer types including 10% of colorectal cancer (CRC). Very interestingly, a recent publication described the pivotal role of the loss of ARID1A in driving CRC wherein its inactivation alone led to the formation of invasive adenocarcinomas in mice. However, surprisingly, in contrast to the expected tumor suppressive role of ARID1A in CRC, we observe that the knockout (KO) of ARID1A in CRC cell lines leads to impaired proliferation. Moreover, subcutaneous xenografts in SCID/SHO mice using ARID1A KO CRC cells did not form more aggressive tumors than their wild type counterparts. One of the most commonly occurring mutations in CRC is in the APC gene, which leads to hyperactive Wnt signaling. Thus CRC progression is typically highly dependent on this pathway. Notably, it is reported that loss of ARID1A in the context of APC mutations results in diminished tumor formation in mice and increased differentiation. This led us to hypothesize that ARID1A is required for Wnt signaling-mediated transcriptional (de)regulation in CRC. To uncover this further, we utilized several publically available ChIP-seq, RNA-seq and ATAC-seq datasets as well as our own ChIP-seq data for ARID1A in the HCT116 cell line. We observe a substantial co-localization of the BAF complex with TCF7L2, a downstream effector of the Wnt signaling pathway, suggesting cooperation between these factors. Further, these sites are also co-occupied by AP1 transcription factors. A crosstalk between the TCF7L2 and AP1 factors has been reported in intestinal tumors. From data available in the ARID1A KO system, we observe a downregulation of potential target genes which are co-occupied at neighboring sites by these factors. Therefore, we suggest that ARID1A plays an important role in the regulation of colorectal cancer relevant genes that are targets of TCF7L2/AP1, thus facilitating a pathway that is most commonly hijacked in colorectal cancer. Citation Format: Madhobi Sen, Feda H. Hamdan, Xin Wang, Jacobe Rapp, Steven A. Johnsen. The role of the BAF complex in Wnt signaling-mediated transcriptional regulation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1472
Store-Operated Calcium Entry: Shaping the Transcriptional and Epigenetic Landscape in Pancreatic Cancer
No full textPancreatic ductal adenocarcinoma (PDAC) displays a particularly poor prognosis and low survival rate, mainly due to late diagnosis and high incidence of chemotherapy resistance. Genomic aberrations, together with changes in the epigenomic profile, elicit a shift in cellular signaling response and a transcriptional reprograming in pancreatic tumors. This endows them with malignant attributes that enable them to not only overcome chemotherapeutic challenges, but to also attain diverse oncogenic properties. In fact, certain genetic amplifications elicit a rewiring of calcium signaling, which can confer ER stress resistance to tumors while also aberrantly activating known drivers of oncogenic programs such as NFAT. While calcium is a well-known second messenger, the transcriptional programs driven by aberrant calcium signaling remain largely undescribed in pancreatic cancer. In this review, we focus on calcium-dependent signaling and its role in epigenetic programs and transcriptional regulation. We also briefly discuss genetic aberration events, exemplifying how genetic alterations can rewire cellular signaling cascades, including calcium-dependent ones
Epigenome Mapping Identifies Tumor-Specific Gene Expression in Primary Rectal Cancer
No full textEpigenetic alterations play a central role in cancer development and progression. The acetylation of histone 3 at lysine 27 (H3K27ac) specifically marks active genes. While chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-seq) analyses are commonly performed in cell lines, only limited data are available from primary tumors. We therefore examined whether cancer-specific alterations in H3K27ac occupancy can be identified in primary rectal cancer. Tissue samples from primary rectal cancer and matched mucosa were obtained. ChIP-seq for H3K27ac was performed and differentially occupied regions were identified. The expression of selected genes displaying differential occupancy between tumor and mucosa were examined in gene expression data from an independent patient cohort. Differential expression of four proteins was further examined by immunohistochemistry. ChIP-seq for H3K27ac in primary rectal cancer and matched mucosa was successfully performed and revealed differential binding on 44 regions. This led to the identification of genes with increased H3K27ac, i.e., RIPK2, FOXQ1, KRT23, and EPHX4, which were also highly upregulated in primary rectal cancer in an independent dataset. The increased expression of these four proteins was confirmed by immunohistochemistry. This study demonstrates the feasibility of ChIP-seq-based epigenome mapping of primary rectal cancer and confirms the value of H3K27ac occupancy to predict gene expression differences
Guidance Navigation and Control for a Mobile Robot using Vision System and Adaptive Particle Filter
No full textThe main goal of this thesis is to present a system for determining a mobile robot’s pose estimation and mapping in unknown environments. This system has the ability to guide, navigate and control the robot based on a vision system. The system utilizes sensor fusion to enhance the accuracy and efficiency of state estimation. The mobile robot employs a stereo camera and to increase the precision and accuracy of the state estimate, a new Adaptive Fuzzy Particle Filter is implemented based on the fuzzy logic which commonly occur in the traditional Particle Filter and prevented them from diverging. The proposal investigated the mobile robot’s characteristics parameters in an unknown environment with varying amounts of particles. The results showed that the sensor noise can be reduced effectively. The mobile robots using PID controlling was introduced. Experimental validation substantiated the resilience and effectiveness of the proposed controller
Strategi Pemasaran Bisnis Travel Umroh Menggunakan Analisis SWOT (Studi Kasus PT. Hamdan Syakuro Alkhoir)
No full textThis research is motivated by the increasingly rapid development of Muslims in the world and in Indonesia in particular. One of the pillars of Islam is the Hajj. If you can afford it, to get to Mecca you need a means of transportation. With good means of transportation, pilgrims can carry out the Hajj and Umrah pilgrimages safely, calmly and without any hassle. This research aims to determine the strengths, weaknesses, opportunities and threats (Strengths, Weakness, Opportunities and Threats) faced, as well as the appropriate marketing strategy to be implemented at PT. Hamdan Syakuro Alkhoir. This research uses a qualitative approach, where field data collection is carried out using interviews and document searches. From the research results that have been explained, it can be concluded that the SWOT analysis of PT. Hamdan Syakuro Alkhoir is guaranteed with a score of 0.4, while the weakness is the limited number of people responsible for distribution (lack of employees) with a score of 0.3. Second SWOT analysis of PT. Hamdan Syakuro Alkhoir regarding external factors for opportunities is the existence of good service with a score of 0.15, while the threat is the existence of competition between the same bureaus with a score of 0.04. The final result is the position of PT. Hamdan Syakuro Alkhoir is currently in quadrant I, namely growth strategy. This result is determined based on the average score on IFAS 2.4 and EFAS 3.31, so that the best alternative strategy for business development, especially the marketing strategy of PT. Hamdan Syakuro Alkhoir with a strength opportunities (SO) strategy is to maintain and improve service quality so that it can increase the opportunities that will be obtained by PT. Hamdan Syakuro Alkhoir. Based on the research conclusions, the author recommends in the form of suggestions, namely, PT. Hamdan Syakuro Alkhoir should implement a growth strategy by maintaining and improving the quality of services at PT. Hamdan Syakuro Alkhoir. Then the identification of strategies from researchers can be included as a strategic consideration for promotion of various service sectors in general in Hajj and Umrah travel services, and especially in PT. Hamdan Syakuro Alkhoir. Apart from being able to increase the value of the PT brand. Hamdan Syakuro Alkhoir, can also strengthen vision. Hamdan Syakuro Alkhoiry is to prioritize service and create comfort and uniqueness for the congregation in worship
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