Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity

Fagnocchi, Luca; Poli, Vittoria; Zippo, Alessio

doi:10.1007/s00018-018-2820-1

Cited by 28 publications

(20 citation statements)

References 177 publications

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“…Indeed, c-Myc binding achieves a peak at the center of the H3K27ac-enriched region among c-Myc-targeted de novo enhancers, which strongly suggests a direct contribution to the deposition of this active histone mark. The down-regulation of GATA3 and ESR1, both of which are master regulators of mammary gland morphogenesis and luminal cell differentiation, is mainly regulated by c-Myc which binds to their cis -regulatory elements [ 51 , 52 ]. Thus, c-Myc-induced oncogenic and epigenetic reprogramming leads to the acquisition of cancer stem-like cells (CSCs)-associated properties and induction of the intra-tumoral heterogeneity.…”

Section: Emerging Roles Of Myc In Terms Of the Carcinogensis Of The Dmentioning

confidence: 99%

Emerging roles of Myc in stem cell biology and novel tumor therapies

Yoshida

2018

J Exp Clin Cancer Res

193

154

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The pathophysiological roles and the therapeutic potentials of Myc family are reviewed in this article. The physiological functions and molecular machineries in stem cells, including embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, are clearly described. The c-Myc/Max complex inhibits the ectopic differentiation of both types of artificial stem cells. Whereas c-Myc plays a fundamental role as a “double-edged sword” promoting both iPS cells generation and malignant transformation, L-Myc contributes to the nuclear reprogramming with the significant down-regulation of differentiation-associated genetic expression. Furthermore, given the therapeutic resistance of neuroendocrine tumors such as small-cell lung cancer and neuroblastoma, the roles of N-Myc in difficult-to-treat tumors are discussed. N-Myc-driven neuroendocrine tumors tend to highly express NEUROD1, thereby leading to the enhanced metastatic potential. Importantly enough, accumulating evidence strongly suggests that c-Myc can be a promising therapeutic target molecule among Myc family in terms of the biological characteristics of cancer stem-like cells (CSCs). The presence of CSCs leads to the intra-tumoral heterogeneity, which is mainly responsible for the therapeutic resistance. Mechanistically, it has been shown that Myc-induced epigenetic reprogramming enhances the CSC phenotypes. In this review article, the author describes two major therapeutic strategies of CSCs by targeting c-Myc; Firstly, Myc-dependent metabolic reprogramming is closely related to CD44 variant-dependent redox stress regulation in CSCs. It has been shown that c-Myc increases NADPH production via enhanced glutaminolysis with a finely-regulated mechanism. Secondly, the dormancy of CSCs due to FBW7-depedent c-Myc degradation pathway is also responsible for the therapeutic resistance to the conventional anti-tumor agents, the action points of which are largely dependent on the operation of the cell cycle. That is why the loss-of-functional mutations of FBW7 gene are expected to trigger “awakening” of dormant CSCs in the niche with c-Myc up-regulation. Collectively, although the further research is warranted to develop the effective anti-tumor therapeutic strategy targeting Myc family, we cancer researchers should always catch up with the current advances in the complex functions of Myc family in highly-malignant and heterogeneous tumor cells to realize the precision medicine.

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Section: Emerging Roles Of Myc In Terms Of the Carcinogensis Of The Dmentioning

confidence: 99%

Emerging roles of Myc in stem cell biology and novel tumor therapies

Yoshida

2018

J Exp Clin Cancer Res

193

154

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“…The β-isomer of hexaclorocyclohexane has not been largely investigated, despite its relatively common geographic distribution [ 3 ] and its physicochemical properties (great stability, environmental persistence, high lipid solubility, bioaccumulation) make it potentially dangerous. A detailed environmental–epidemiological study carried out on exposed population living throughout the “Valle del Sacco”—south of Rome [ 23 , 24 ], as well as others reported by different countries [ 42 ], indicates correlations between the incidence of a wide range of diseases and the occurrence of β-HCH contamination.…”

Section: Discussionmentioning

confidence: 99%

“…Organochlorine compounds are widely distributed in the environment and several studies link their basic molecular mechanism of endocrine disruption [ 1 , 2 ] with the onset of many pathological conditions such as chronic inflammatory processes, cardiovascular diseases, neurological and metabolic disorders, and oncogenesis [ 3 , 4 , 5 ]. The toxicity of organochlorine compounds is related to their physicochemical properties, because these pollutants belong to a group of organic compounds, known as “persistent organic pollutants” (POPs), that are resistant to degradation or biodegradation and that can be bioaccumulated into adipose tissue because of their lipotropic properties and great stability [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

STAT3, a Hub Protein of Cellular Signaling Pathways, Is Triggered by β-Hexaclorocyclohexane

Rubini

Altieri

Chichiarelli

et al. 2018

IJMS

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Background: Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption. Among OCPs, particular attention was focused on the effects of β-hexaclorocyclohexane (β-HCH), a widely common pollutant. A detailed epidemiological study carried out on exposed population in the “Valle del Sacco” found correlations between the incidence of a wide range of diseases and the occurrence of β-HCH contamination. Taking into account the pleiotropic role of the protein signal transducer and activator of transcription 3 (STAT3), its function as a hub protein in cellular signaling pathways triggered by β-HCH was investigated in different cell lines corresponding to tissues that are especially vulnerable to damage by environmental pollutants. Materials and Methods: Human prostate cancer (LNCaP), human breast cancer (MCF-7 and MDA-MB 468), and human hepatoma (HepG2) cell lines were treated with 10 μM β-HCH in the presence or absence of specific inhibitors for different receptors. All samples were subjected to analysis by immunoblotting and RT-qPCR. Results and Conclusions: The preliminary results allow us to hypothesize the involvement of STAT3, through both its canonical and non-canonical pathways, in response to β-HCH. Moreover, we ascertained the role of STAT3 as a master regulator of energy metabolism via the altered expression and localization of HIF-1α and PKM2, respectively, resulting in a Warburg-like effect.

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“…How can oncogenic enhancers be maintained? Which molecules are involved in the initiation and progression of cancer genotypes with expanding CSCs of each tumor type [164]? CRISPR-mediated epigenome editing may be a promising technique to identify the key cis -elements in the genomes of CSCs [165–168].…”

Section: Obstacles To Cancer Cell Reprogrammingmentioning

confidence: 99%

Potential application of cell reprogramming techniques for cancer research

Saito

Lin

Nakamura

et al. 2018

Cell. Mol. Life Sci.

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The ability to control the transition from an undifferentiated stem cell to a specific cell fate is one of the key techniques that are required for the application of interventional technologies to regenerative medicine and the treatment of tumors and metastases and of neurodegenerative diseases. Reprogramming technologies, which include somatic cell nuclear transfer, induced pluripotent stem cells, and the direct reprogramming of specific cell lineages, have the potential to alter cell plasticity in translational medicine for cancer treatment. The characterization of cancer stem cells (CSCs), the identification of oncogene and tumor suppressor genes for CSCs, and the epigenetic study of CSCs and their microenvironments are important topics. This review summarizes the application of cell reprogramming technologies to cancer modeling and treatment and discusses possible obstacles, such as genetic and epigenetic alterations in cancer cells, as well as the strategies that can be used to overcome these obstacles to cancer research.

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Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity

Cited by 28 publications

References 177 publications

Emerging roles of Myc in stem cell biology and novel tumor therapies

Emerging roles of Myc in stem cell biology and novel tumor therapies

STAT3, a Hub Protein of Cellular Signaling Pathways, Is Triggered by β-Hexaclorocyclohexane

Potential application of cell reprogramming techniques for cancer research

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