An Integrated Genomic and Epigenomic Approach Predicts Therapeutic Response to Zebularine in Human Liver Cancer

Andersen, Jesper B.; Factor, Valentina M.; Marquardt, Jens U.; Raggi, Chiara; Lee, Yun Han; Seo, Daekwan; Conner, Elizabeth A.; Thorgeirsson, Snorri S.

doi:10.1126/scitranslmed.3001338

Cited by 88 publications

(91 citation statements)

References 48 publications

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“…Marquardt and colleagues noted a significant reduction of SIRT6 in HCC specimens based on analysis of a publicly available cancer microarray database (24). These researchers further observed a reduction in SIRT6 mRNA expression in 45% (24/53) of HCC specimens from their recently published HCC database (24,25). In contrast with their findings, by analyzing SIRT6 expression in 101 paired frozen HCC tissues and 60 paired paraffin-embedded sections, we convincingly showed that both SIRT6 mRNA and protein levels were significantly upregulated in the majority of HCC tissues compared with adjacent nontumoral liver tissues.…”

Section: Discussionmentioning

confidence: 94%

SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway

Ran

Chen

Zhang

et al. 2016

Clinical Cancer Research

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Purpose: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC).Experimental Design: The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo.Results: SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P ¼ 0.02), tumor size (P ¼ 0.02), vascular invasion (P ¼ 0.004), and shorter survival (P ¼ 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro. At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples.Conclusions: SIRT6 is an important protumorigenic factor in liver carcinogenesis. Thus, the therapeutic targeting of SIRT6 may offer options for HCC treatment.

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Section: Discussionmentioning

confidence: 94%

SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway

Ran

Chen

Zhang

et al. 2016

Clinical Cancer Research

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“…Indeed, indications are clear that drug-resistant tumor cells display an upregulation of the oncogenic E2F1-signaling network, which mediates therapy evasion (25). Microcephalin 1 (MCPH1) cooperates with E2F1 to induce genes involved in DNA repair and apoptosis upon chemotherapy in normal and tumor cells through complex formation on the promoters of these genes (26).…”

Section: E2f1 Mediates Chemoresistancementioning

confidence: 99%

The Dark Side of E2F1: In Transit beyond Apoptosis

2012

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E2F1 plays a critical role in cell-cycle progression and the induction of apoptosis in response to DNA damage. The latest evidence has uncovered that this tumor suppressor is most relevant for cancer progression and chemoresistance. Increased abundance of E2F1 triggers invasion and metastasis by activating growth receptor signaling pathways, which in turn promote an antiapoptotic tumor environment. The data shed light on the molecular mechanisms underlying E2F1-induced prometastatic activity and predict its radical switch from a mediator of cell death toward an accelerator of tumor progression. This raises the perspective of new drug targets at late-stage cancer. Cancer Res; 72(3); 571-5. Ó2012 AACR. Expanding the E2F ParadigmMore than 2 decades of experimentation link E2F activity to retinoblastoma tumor suppressor (RB)-dependent cell-cycle control. E2F proteins are situated downstream of growth factor signaling cascades, where they regulate genes required for cellcycle progression by acting either as transcriptional activators or as repressors. Activating members of the E2F family (E2F1-3) can contribute to oncogenic transformation of rodent embryonic fibroblasts and tumorigenesis when overexpressed. The absence of activating E2Fs in flies or mammalian fibroblasts causes cell-cycle arrest, but this block is alleviated by removing repressive E2F or the tumor suppressor p53. The idea that E2F function is indispensible for cell proliferation is under debate and has dominated discussions for years.Recent work from Chen and colleagues in knockout mouse models is challenging the current E2F paradigm. The researchers showed that in retinal progenitor cells deficient for all activating E2Fs, proliferation is bypassed by MYCN (1). Instead, activating E2Fs have an unexpected prosurvival role during retinal development via induction of the apoptosis inhibitory Sirt1-p53 axis. Similar results were obtained from transgenic mice with conditional E2F triple deficiency in embryonic stem cells. Thus, E2F1-3 function is, contrary to the current view, expendable for cell division in the majority of cell types present during organ development and embryogenesis, but it is necessary for suppressing cell death (2). Although these studies were accomplished in normal tissues, they might teach us a lesson about the role of E2Fs in cancer. On the basis of recently published research, we should challenge the prevailing view that cell proliferation is the major and most important oncogenic mechanism of E2Fs. Even if this function may have evolved during tumor development, we are only beginning to understand how E2F family proteins participate in other, as yet uncharted, biologic processes that contribute to tumor promotion and, more importantly, to tumor progression. Switching Duties: A Tumor Suppressor Contributes to Cancer ProgressionIn the past, E2F1 in particular was recognized as a strong regulator of apoptosis after DNA damage in all types of human cancer (3). Most human tumors harbor functionally inactivated RB, resulting i...

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“…On the other hand, brivanib, which targets VEGFR, PDGFR and FGFR, also failed to prolong OS (Table 1) in a phase III trial conducted to investigate its efficacy as a first line therapy even though it had a more favorable toxicity profile than sorafenib [89,90]. Moreover, another phase III, randomized, placebo-controlled study investigated the efficacy of brivanib after sorafenib failure and the authors reported that, in comparison to placebo, brivanib resulted in a longer median TTP but insignificant increase in the OS (Table 1) [91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108].…”

Section: Anti-angiogenic Agentsmentioning

confidence: 99%

“…Such results may open new avenues for the intervention and management of HCC. For instance, Andersen et al [104] showed that treatment with the DNMT inhibitor zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines were associated with up regulation of oncogenic networks (e.g. E2F1, Myc, and TNF) driving liver cancer growth in vitro and in preclinical mouse models.…”

Section: Deoxyribonucleic Acid Methylation (Dnmt) Inhibitorsmentioning

confidence: 99%

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

Mekuria¹,

Abdi²

2017

J Cancer Sci Ther

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Hepatocellular Carcinoma (HCC) is a common type of primary liver cancer. According to the recent world cancer report, the disease ranked as the sixth most common cancer worldwide and the third largest cause of cancer-related death. Deregulation of numerous signaling pathways have been implicate in pathogenesis of HCC, including IGF, EGF/TGF, HGF/cMet, WNT, Hedgehog, notch, hippo, VEGF, PDGF, and FGF. Besides, intracellular mediators such as MAPK and PI3K/AKT/mTOR play a role in HCC development and progression. Currently sorafenib is the only molecularly targeted drug available to treat advanced HCC. It only extends survival by a matter of months. Moreover, there is no alternative agent for patients progressing under treatment with sorafenib. Thus, there remains a critical need for both continued molecular characterization and aggressive drug development. This review provided and updated appraisal of the deregulated signaling and epigenetic pathways, targeted therapeutics that is being investigated and possible challenges in drug development for HCC. Nevertheless, c-Met over-expression was reported to be related to increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition [26]. Pathways related to neo-angiogenesisHigh vascularization is a hallmark of human HCC [8]. This angiogenesis process relies on autocrine and paracrine interactions between tumor cells, vascular endothelial cells, and pericytes. Tumor cells release pro-angiogenic factors in response to hypoxic conditions and nutrient deprivation and thus activate endothelial cells [27]. Activated endothelial cells break down extracellular matrix and basement membrane which result in a release of angiogenic factors which includes VEGF, FGF, PDGF, and TGF β [16]. These angiogenic factors in turn activate endothelial cells through TKR and their intracellular mediator's MAPK and PI3K/Akt/mTOR pathways, which lead to proliferation and migration of endothelial cells to form a new tubular structure and lumen for new vessels and finally, pericytes are activated and recruited to stabilize the new blood vessels [27,28]. has become a potential investigating area of research to identify target(s) to inhibit proliferation of HCC and metastasis. IGF pathwayThe pathway consists of circulating ligands IGF-I, IGF-II, and the receptor IGF-IR. It has been known for its involvement in the regulation of cell growth and energy metabolism [17]. According to studies, overexpression of IGF-II and IGF-IR has been implicated in cell proliferation and inhibition of apoptosis [18]. In support of this, low expression of IGF I and progressive increase in the level of expression of IGF-IR, IGF-II, and IGF substrates during the hepatocarcinogenesis process was detected at mRNA and protein level, which was associated with cell increased proliferation and reduced apoptosis has been observed in HCC cell lines and rat models as well as in human HCC samples [18]. Other studies also indicated that the major tumorpromoting e...

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An Integrated Genomic and Epigenomic Approach Predicts Therapeutic Response to Zebularine in Human Liver Cancer

Cited by 88 publications

References 48 publications

SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway

SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway

The Dark Side of E2F1: In Transit beyond Apoptosis

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

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