Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

Chiang, Yan Ting; Gout, Peter W.; Wang, Yuzhuo

doi:10.4103/1008-682x.122875

Cited by 11 publications

(7 citation statements)

References 31 publications

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“…HOXC6 is involved in epithelial cell proliferation, and loss of this gene induces apoptosis in prostate cancer cells [30, 31]. DLX1 encodes a distal-less homeobox 1 protein that is reported to drive prostate cancer metastasis [32]. Upon independent knockdown of these genes in C42B prostate cancer cells, we found that for HOXC6, the top GO terms for downregulated genes were mitotic cell cycle and cell cycle (e.g., CDKN2C , CDK16 , IGFBP3 ), and for DLX1, genes involved in proliferation and androgen-responsive genes were enriched in downregulated genes (e.g., CDCA7 , MAGOH , MAD2L1 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits

Rhie

Guo

Tak

et al. 2016

Epigenetics & Chromatin

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BackgroundAlthough technological advances now allow increased tumor profiling, a detailed understanding of the mechanisms leading to the development of different cancers remains elusive. Our approach toward understanding the molecular events that lead to cancer is to characterize changes in transcriptional regulatory networks between normal and tumor tissue. Because enhancer activity is thought to be critical in regulating cell fate decisions, we have focused our studies on distal regulatory elements and transcription factors that bind to these elements.ResultsUsing DNA methylation data, we identified more than 25,000 enhancers that are differentially activated in breast, prostate, and kidney tumor tissues, as compared to normal tissues. We then developed an analytical approach called Tracing Enhancer Networks using Epigenetic Traits that correlates DNA methylation levels at enhancers with gene expression to identify more than 800,000 genome-wide links from enhancers to genes and from genes to enhancers. We found more than 1200 transcription factors to be involved in these tumor-specific enhancer networks. We further characterized several transcription factors linked to a large number of enhancers in each tumor type, including GATA3 in non-basal breast tumors, HOXC6 and DLX1 in prostate tumors, and ZNF395 in kidney tumors. We showed that HOXC6 and DLX1 are associated with different clusters of prostate tumor-specific enhancers and confer distinct transcriptomic changes upon knockdown in C42B prostate cancer cells. We also discovered de novo motifs enriched in enhancers linked to ZNF395 in kidney tumors.ConclusionsOur studies characterized tumor-specific enhancers and revealed key transcription factors involved in enhancer networks for specific tumor types and subgroups. Our findings, which include a large set of identified enhancers and transcription factors linked to those enhancers in breast, prostate, and kidney cancers, will facilitate understanding of enhancer networks and mechanisms leading to the development of these cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0102-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits

Rhie

Guo

Tak

et al. 2016

Epigenetics & Chromatin

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“…Knockdown of TIM in hepatocellular carcinoma cells induces apoptosis, arrests cell cycle in the G2 phase, and inhibits cell migration by perturbing the interaction with eukaryotic elongation factor 1A2 (EEF1A2) [ 11 ]. Moreover, TIM is upregulated in tissue in metastatic prostate cancer, and TIM knockdown in prostate cancer cell PC3M suppresses cell migration [ 13 ]. More recently, alteration of TIM expression in breast cancer has been reported to be associated with advanced tumor stage and poorer prognosis [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

TIMELESS contributes to the progression of breast cancer through activation of MYC

et al. 2017

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BackgroundBreast cancer is the most common malignancy and the leading cause of cancer death among women. TIMELESS (TIM), a circadian rhythm regulator, has been recently implicated in the progression of human cancer. However, the role of TIM in the progression of breast cancer has not been well-characterized.MethodsImmunohistochemistry (IHC) staining was used to examine TIM levels in breast cancer specimens. Mammosphere formation analysis and side population analysis were used to examine the effect of TIM on the self-renewal of breast cancer stem cells. A wound healing assay and a Transwell assay were used to determine the role of TIM in breast cancer cell migration and invasion. A soft agar growth assay in vitro and tumorigenicity in vivo were used to determine the role of TIM in tumorigenicity.ResultsTIM levels in both breast cancer cell lines and tissues were significantly upregulated. Patients with high TIM had poorer prognosis than patients with low TIM. Overexpression of TIM dramatically enhanced, while knockdown of TIM suppressed the self-renewal of cancer stem cells (CSCs), cell invasion and migration abilities of breast cancer cells in vitro. Moreover, overexpression of TIM significantly augmented, while knockdown of TIM reduced the tumorigenicity of breast cancer cells in vivo. Mechanism studies revealed that TIM upregulated the expression and the trans-activity of the well-known oncogene MYC. Inhibition of MYC significantly blocked the effects of TIM on CSC population, cell invasion and anchor-independent cell growth.ConclusionTIM plays an important role in promoting breast cancer progression and may represent a novel therapeutic target for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0838-1) contains supplementary material, which is available to authorized users.

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“…Several previous reports show the involvement of TIM in human cancers [19] of many different organs, including lung [20], breast [21][22][23], liver [24], prostate [25], colon [26], kidney [27], bladder [28], pancreas [29], and blood [30]. Sjoblom et al [31] showed that TIM mutations are involved in breast cancer.…”

Section: Research Paper Wwwoncotargetcommentioning

confidence: 99%

Knock-down of the TIM/TIPIN complex promotes apoptosis in melanoma cells

et al. 2020

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The Timeless (TIM) and it's interacting partner TIPIN protein complex is well known for its role in replication checkpoints and normal DNA replication processes.Recent studies revealed the involvement of TIM and TIPIN in human malignancies; however, no evidence is available regarding the expression of the TIM/TIPIN protein complex or its potential role in melanoma. Therefore, we investigated the role of this complex in melanoma. Toassess the role of the TIM/TIPIN complex in melanoma, we analyzed TIM/ TIPIN expression data from the publicly accessible TCGA online database, Western blot analysis, and RT-qPCR in a panel of melanoma cell lines. Lentivirus-mediated TIM/ TIPIN knockdown in A375 melanoma cells was used to examine proliferation, colony formation, and apoptosis. A xenograft tumor formation assay was also performed. The TIM/TIPIN complex is frequently overexpressed in melanoma cells compared to normal melanocytes. We also discovered that the overexpression of TIM and TIPIN was significantly associated with poorer prognosis of melanoma patients. Furthermore, we observed that shRNA-mediated knockdown of TIM and TIPIN reduced cell viability and proliferation due to the induction of apoptosis and increased levels of γH2AX, a marker of DNA damage. In a xenograft tumor nude mouse model, shRNA-knockdown of TIM/TIPIN significantly reduced tumor growth. Our results suggest that the TIM/TIPIN complex plays an important role in tumorigenesis of melanoma, which might reveal novel approaches for the development of new melanoma therapies. Our studies also provide a beginning structural basis for understanding the assembly of the TIM/TIPIN complex. Further mechanistic investigations are needed to determine the complex's potential as a biomarker of melanoma susceptibility. Targeting TIM/TIPIN might be a potential therapeutic strategy against melanoma.

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Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

Cited by 11 publications

References 31 publications

Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits

Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits

TIMELESS contributes to the progression of breast cancer through activation of MYC

Knock-down of the TIM/TIPIN complex promotes apoptosis in melanoma cells

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