An oncogenic enhancer encodes selective selenium dependency in AML

Eagle, Kenneth; Jiang, Yajian; Shi, Xiangguo; Li, Minhua; Obholzer, Nikolaus P.; Hu, Tianyuan; Perez, Monika W.; Koren, Jošt Vrabič; Kitano, Ayumi; Yi, Joanna; Lin, Charles Y.; Nakada, Daisuke

doi:10.1016/j.stem.2022.01.003

Cited by 18 publications

(11 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This implies that enhancer-mediated INSIG2 boosting provides a compensatory mechanism for the loss of INSIG1 in HepG2, offering a plausible explanation for the unique essentiality of INSIG2 in HepG2. Further supporting the functional relevance of enhancer-dependent boosting, a recent study showed that an oncogenic enhancer increases the expression of SEPHS2 in acute myeloid leukemia (AML) and creates unique sensitivity of AML cells to dietary selenium restriction 54 . Enhancer deletion only partially (<50%) reduces SEPHS2 expression, but significantly impairs was not certified by peer review) is the author/funder.…”

Section: Enhancer-dependent Boosting Is Functionally Consequentialmentioning

confidence: 93%

“…AML cell proliferation 54 . Our work independently confirms enhancer-dependent boosting (~50%) of SEPHS2 in AML-derived KG-1, but not in HCT116, SH-SY5Y, or Jurkat (Extended Data Fig.…”

Section: Enhancer-dependent Boosting Is Functionally Consequentialmentioning

confidence: 99%

“…Previously, it remained unclear why deletion of the enhancer only partially reduced SEPHS2 expression in AML cells, and why deletion of the same enhancer did not decrease SEPHS2 expression in non-AML cells 54 . We find that SEPHS2 can be expressed enhancer-independently, and its expression can be boosted cell-type-specifically, by distinctly positioned enhancers, offering plausible answers to the unresolved questions 54 (Supplementary note 2). Enhancer and PRE strengths are tuned independently and cell-type-specifically Next, we sought to quantitatively assess the relative impact of enhancers and PREs in gene activation.…”

Section: Enhancer-dependent Boosting Is Functionally Consequentialmentioning

confidence: 99%

“…Pioneering factors can bind to closed chromatin, but we are not aware of concrete evidence showing a major contribution of closed enhancers to native gene regulation, without acquiring accessibility under the conditions in which they are active. Supplementary note 2 Deletion of the oncogenic SEPHS2 enhancer did not impair expression in normal hematopoietic cells or cells that originated from other tissues 54 . Our work independently confirms this finding and shows that the enhancer boosts (~50%) SEPHS2 expression in the AML-derived KG-1, but not in HCT116, SH-SY5Y, or Jurkat (Extended Data Fig.…”

Section: Supplementary Notementioning

confidence: 99%

See 3 more Smart Citations

The logic of native enhancer-promoter compatibility and cell-type-specific gene expression variation

Narita

Higashijima

Kilic

et al. 2022

Preprint

View full text Add to dashboard Cite

Cis-regulatory enhancers are essential for differential expression of developmental and housekeeping genes. However, the specificity of native mammalian enhancers and how it shapes cell-type-specific gene expression landscapes remain largely unknown. We show that endogenous enhancers are broadly compatible with the promoters of developmental and housekeeping genes. Broad enhancer compatibility affords ‘retrofitting’ new regulatory capabilities to housekeeping genes that evolved before the advent of enhancers. This enables cell-type-specific tuning of ubiquitously expressed genes. Segregation between enhancer-dependent and –independent type regulation is blurred. Within the same cell type, a single promoter can be activated by enhancers and non-enhancer promoter-regulatory elements (PREs). It is the tunable and integrated strengths of enhancers and PREs that quantitatively shape gene expression landscapes, within and across cell types. Our findings have broad implications for understanding cell-type-specific quantitative gene expression variation, as well as the emergence and rewiring of gene regulatory networks in disease and organismal evolution.

show abstract

Section: Enhancer-dependent Boosting Is Functionally Consequentialmentioning

confidence: 93%

“…AML cell proliferation 54 . Our work independently confirms enhancer-dependent boosting (~50%) of SEPHS2 in AML-derived KG-1, but not in HCT116, SH-SY5Y, or Jurkat (Extended Data Fig.…”

Section: Enhancer-dependent Boosting Is Functionally Consequentialmentioning

confidence: 99%

Section: Enhancer-dependent Boosting Is Functionally Consequentialmentioning

confidence: 99%

Section: Supplementary Notementioning

confidence: 99%

See 2 more Smart Citations

The logic of native enhancer-promoter compatibility and cell-type-specific gene expression variation

Narita

Higashijima

Kilic

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Recently, Eagle K et al integrated pan-cancer genetic dependency data with that of a comprehensive enhancer landscape and identified SEPHS2 , a selenoprotein biosynthesis gene, as a highly AML-selective dependency encoded by a Myb-regulated oncogenic enhancer. The suppression of the SEPHS2 -regulated production of selenoproteins by diet selectively renders AML susceptible to oxidative stress without affecting normal hematopoiesis [ 55 ]. Overall, the current literature highlights the potential role of selenoproteins and selenium metabolism in different cancers including hematopoietic malignancies.…”

Section: Regulation Of Signaling Pathways By Selenium In Cancermentioning

confidence: 99%

Therapeutic Benefits of Selenium in Hematological Malignancies

Ehudin

Golla

Trivedi

et al. 2022

IJMS

View full text Add to dashboard Cite

Supplementing chemotherapy and radiotherapy with selenium has been shown to have benefits against various cancers. This approach has also been shown to alleviate the side effects associated with standard cancer therapies and improve the quality of life in patients. In addition, selenium levels in patients have been correlated with various cancers and have served as a diagnostic marker to track the efficiency of treatments or to determine whether these selenium levels cause or are a result of the disease. This concise review presents a survey of the selenium-based literature, with a focus on hematological malignancies, to demonstrate the significant impact of selenium in different cancers. The anti-cancer mechanisms and signaling pathways regulated by selenium, which impart its efficacious properties, are discussed. An outlook into the relationship between selenium and cancer is highlighted to guide future cancer therapy development.

show abstract