PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

Toska, Eneda; Castel, Pau; Chhangawala, Sagar; Arruabarrena-Aristorena, Amaia; Chan, Carmen Wing Han; Hristidis, V.; Cocco, Emiliano; Sallaku, Mirna; Xu, Guotai; Park, Jane; Minuesa, Gerard; Shifman, Sophie; Socci, Nicholas D.; Koche, Richard P.; Leslie, Christina; Scaltriti, Maurizio; Baselga, José

doi:10.1016/j.celrep.2019.02.111

Cited by 51 publications

(58 citation statements)

References 50 publications

(88 reference statements)

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“…Thus, a negative feedback loop activates SGK1 to promote chromatin-based regulation of ER-dependent gene expression (Figure 2). Given that high levels of active SGK1 would inhibit ER activity making cells less dependent on the ER response [47], we speculate that SGK1 could be another important mediator of resistance not only to PI3K inhibitors, as we have previously reported [33], but also to endocrine therapies. Other hormone nuclear receptors such as PR or retinoic acid receptor [48, 49] have been previously linked to affect ER transcriptional activity, and their gene signatures are elevated by PI3K kinase inhibition [46].…”

Section: Crosstalk Between Er and Pi3k Pathwaymentioning

confidence: 78%

Overview of the relevance of PI3K pathway in HR-positive breast cancer

2019

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One of the hallmarks of hormone receptor (HR)-positive breast cancer is its dependence on the phosphatidylinositol-3-kinase (PI3K) pathway. Here, we review the epidemiologic, functional, and pharmacologic interactions between oncogenic PI3K and the estrogen receptor (ER). We discuss the epidemiology of PI3K pathway alterations, mechanisms of resistance to PI3K inhibitors, and the current mechanistic landscape of crosstalk between PI3K and ER, which provide the rationale for dual ER and PI3K inhibition and is now a standard of care in the treatment of ER+ PIK3CA-mutant metastatic breast cancer. We outline newer studies in this field that delineate the clinically relevant overlaps between PI3K and parallel signaling pathways, insulin signaling, and ER epigenetic modifiers. We also identify several caveats with the current data and propose new strategies to overcome these bottlenecks.

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Section: Crosstalk Between Er and Pi3k Pathwaymentioning

confidence: 78%

Overview of the relevance of PI3K pathway in HR-positive breast cancer

2019

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“…elevated SGK's may be a biomarker of resistance to the concomitant inhibition of PI3K and ER. 10 Moreover, our observations provide mechanistic understanding of ER regulation by the PI3K signaling and underscore the relevance of the chromatin state in connecting the oncogenic signaling responses with gene activity. (A) AKT1 (also known as protein kinase B, PKB), phosphorylates the H3K4 histone lysine methyltransferase KMT2D at S1331 and negatively regulates its activity leading to a repression of ER, FOXA1 (Forkhead Box A1), and PBX1 (PBX Homeobox 1) transcriptional regulatory network recruitment and attenuation of ER-dependent transcription (AKT1-dependent mechanism).…”

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confidence: 67%

“…In summary, we and others have highlighted the importance of elucidating the overlooked role of SGK's in cancer and therapy response. [8][9][10] For instance, previous studies have shown SGK's to be an important mediator of resistance to PI3K inhibitors 8,9 and, in our recent work, we speculate that a b Figure 1. AKT1 and SGK1-dependent mechanism/s of estrogen receptor (ER) regulation by KMT2D.…”

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confidence: 67%

“…In a recent study, 10 we found that in ER+ breast cancer cells treated with PI3Kα inhibitors, transcriptionally upregulated SGK1 phosphorylates KMT2D, attenuates its activity and recruitment, and subsequently downregulates ERdependent transcription. We demonstrated that the SGK's transcription and protein levels are enhanced upon PI3Kα inhibition through increased occupancy of ER and phosphorylated (S5) Pol II, a marker of transcriptional activation, at the promoters of SGKs.…”

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confidence: 82%

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Chromatin regulation at the intersection of estrogen receptor and PI3K pathways in breast cancer

Castel

Toska

2019

Molecular & Cellular Oncology

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Estrogen Receptor (ER) and the phosphoinositide 3-kinase (PI3K) pathways participate in regulatory crosstalk in breast cancer. We identified that chromatin regulation is at the intersection of oncogenic PI3K and ER. The PI3K effectors AKT, also known as protein kinase B (PKB), and SGK (serum/glucocorticoid-regulated kinase) play a redundant role by phosphorylating the chromatin regulator KMT2D and modulating ER activity and therapy resistance.

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“…mTORC2 exerts its epigenetic function by activation of the AKT and SGK1 proteins. The effect of these proteins on epigenetic regulation is the inhibition of KMT2D, which is a histone methyltransferase specifically targeting H3K4 (Figure 2) (43). Inhibition of KMT2D has been shown to have anti-tumor effects in some cancers by not allowing the FOXA1-PBX-ER complex to access the DNA for transcription (44).…”

Section: Heritable Epigenetic Modifications Acquired Through Microenvmentioning

confidence: 99%

Causes and Consequences of Variable Tumor Cell Metabolism on Heritable Modifications and Tumor Evolution

et al. 2020

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When cancer research advanced into the post-genomic era, it was widely anticipated that the sought-after cure will be delivered promptly. Instead, it became apparent that an understanding of cancer genomics, alone, is unable to translate the wealth of information into successful cures. While gene sequencing has significantly improved our understanding of the natural history of cancer and identified candidates for therapeutic targets, it cannot predict the impact of the biological response to therapies. Hence, patients with a common mutational profile may respond differently to the same therapy, due in part to different microenvironments impacting on gene regulation. This complexity arises from a feedback circuit involving epigenetic modifications made to genes by the metabolic byproducts of cancer cells. New insights into epigenetic mechanisms, activated early in the process of carcinogenesis, have been able to describe phenotypes which cannot be inferred from mutational analyses per se. Epigenetic changes can propagate throughout a tumor via heritable modifications that have long-lasting consequences on ensuing phenotypes. Such heritable epigenetic changes can be evoked profoundly by cancer cell metabolites, which then exercise a broad remit of actions across all stages of carcinogenesis, culminating with a meaningful impact on the tumor's response to therapy. This review outlines some of the cross-talk between heritable epigenetic changes and tumor cell metabolism, and the consequences of such changes on tumor progression.

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PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression

Cited by 51 publications

References 50 publications

Overview of the relevance of PI3K pathway in HR-positive breast cancer

Overview of the relevance of PI3K pathway in HR-positive breast cancer

Chromatin regulation at the intersection of estrogen receptor and PI3K pathways in breast cancer

Causes and Consequences of Variable Tumor Cell Metabolism on Heritable Modifications and Tumor Evolution

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