MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome

Qiu, Zhi Jun; An, Lin; Jiang, Shoulei; Elkashef, Sara M.; Myers, Jamie; Srikantan, Subramanya; Sasi, Binu K.; Cao, John Z.; Godley, Lucy A.; Rakheja, Dinesh; Lyu, Yingli; Zheng, Siyuan; Madesh, Muniswamy; Shiio, Yuzuru; Dahia, Patricia L.M.; Aguiar, Ricardo C.T.

doi:10.1016/j.chembiol.2020.02.002

Cited by 21 publications

(45 citation statements)

References 68 publications

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“…Thus, to explore the mechanism(s) by which cAMP induces PD-L1 transcription/expression, we first investigated if through PKA/CREB, cAMP could directly modulate PD-L1 transcription. Using the “regulatory function” of the UCSC browser and Ensembl, as we reported before 35 , and the ConSite web interface for prediction of regulatory elements 38 , we mapped five putative CRE sites to the well-characterized PD-L1 promoter 34 ( Fig. S2 ).…”

Section: Resultsmentioning

confidence: 99%

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Regulation of PD-L1 expression is a novel facet of cyclic-AMP-mediated immunosuppression

et al. 2020

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Cyclic-AMP (cAMP) exerts suppressive effects in the innate and adaptive immune system. The PD-1/PD-L1 immune checkpoint down-regulates T-cell activity. Here, we examined if these two immunosuppressive nodes intersect. Using normal and malignant lymphocytes from humans, and the phosphodiesterase 4b (Pde4b) knockout mouse, we found that cAMP induces PD-L1 transcription and protein expression. Mechanistically, we discovered that the cAMP effectors PKA and CREB induce the transcription/secretion of IL-10, IL-8 and IL-6, which initiate an autocrine loop that activates the JAK/STAT pathway and ultimately increase PD-L1 expression in the cell surface. This signaling axis is disarmed at two specific nodes in subsets of diffuse large B cell lymphoma, which may help explain the variable PD-L1 expression in these tumors. In vivo, we found that despite its immunosuppressive attributes, the PDE4 inhibitor roflumilast did not decrease the clinical activity of checkpoint inhibitors, an important clinical observation given the approved use of these agents in multiple diseases. In summary, we discovered that PD-L1 induction is a part of the repertoire of immunosuppressive actions mediated by cAMP, defined a cytokine-mediated autocrine loop that executes this action and, reassuringly, showed that PDE4 inhibition does not antagonize immune checkpoint blockade in an in vivo syngeneic lymphoma model.

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Section: Resultsmentioning

confidence: 99%

“…A PD-L1 promoter reporter construct (pGL3-PD-L1–3kb) was described before 34 , and luciferase and beta-galactosidase quantified as we reported 35 .…”

Section: Methodsmentioning

confidence: 99%

Regulation of PD-L1 expression is a novel facet of cyclic-AMP-mediated immunosuppression

et al. 2020

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“…Other analytical platforms also contribute to improved diagnosis and classification, when integrated with sequencing, transcription and immunohistochemical analyses. Epigenetic (especially DNA methylation profiling, but also analysis of posttranslational modifications) and metabolite profiling can help to narrow down the classes of possible susceptibility gene mutations, as well as potential consequences of candidate variants [19,50,59,60].…”

Section: A Workflow To Identify a Driver Mutation In Ppglsmentioning

confidence: 99%

Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

Flores¹,

Estrada-Zuniga²,

Thallapureddy³

et al. 2021

Cancers

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Pheochromocytomas and paragangliomas are rare tumors of neural crest origin. Their remarkable genetic diversity and high heritability have enabled discoveries of bona fide cancer driver genes with an impact on diagnosis and clinical management and have consistently shed light on new paradigms in cancer. In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior.

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“…Another interesting example is where Qiu et al., [ 113 ] studied MYC overexpressing tumors. The authors show that MYC regulates the expression of the mitochondrial enzymes D2HGDH and L2HGDH.…”

Section: Self‐reinforcing Loops Operate In Cancer Chromatin Regulatiomentioning

confidence: 99%

Cause and effect in epigenetics – where lies the truth, and how can experiments reveal it?

Klutstein

2020

BioEssays

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Epigenetic changes are implicated in aging and cancer. Sometimes, it is clear whether the causing agent of the condition is a genetic factor or epigenetic. In other cases, the causative factor is unclear, and could be either genetic or epigenetic. Is there a general role for epigenetic changes in cancer and aging? Here, I present the paradigm of causative roles executed by epigenetic changes. I discuss cases with clear roles of the epigenome in cancer and aging, and other cases showing involvement of other factors. I also present the possibility that sometimes causality is difficult to assign because of the presence of self‐reinforcing loops in epigenetic regulation. Such loops hinder the identification of the causative factor. I provide an experimental framework by which the role of the epigenome can be examined in a better setting and where the presence of such loops could be investigated in more detail.

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MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome

Abstract: Highlights d MYC directly induces the transcription of D2HGDH and L2HGDH d The MYC D2HGDH/L2HGDH interplay influences intermediary metabolism d The MYC-D2HGDH/L2HGDH axis activates TET and RNA demethylases d MYC-expressing B cell lymphomas display hypomethylated and active enhancers

Cited by 21 publications

References 68 publications

Regulation of PD-L1 expression is a novel facet of cyclic-AMP-mediated immunosuppression

Regulation of PD-L1 expression is a novel facet of cyclic-AMP-mediated immunosuppression

Insights into Mechanisms of Pheochromocytomas and Paragangliomas Driven by Known or New Genetic Drivers

Cause and effect in epigenetics – where lies the truth, and how can experiments reveal it?

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