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LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (ChIP-Seq)

ABSTRACT: Genome-wide binding/occupancy profiling by high throughput sequencing

ORGANISM(S): Homo sapiens

PROVIDER: GSE109492 | GEO | 2018/03/12

REPOSITORIES: GEO

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LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia.

Project description:The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF. We also found that MEF2C-dependent leukemias are sensitive to on-target chemical inhibition of SIK activity. This study reveals a chemical strategy to block MEF2C function in AML, highlighting how an oncogenic TF can be disabled by targeting of upstream kinases.

| S-EPMC5856641 | biostudies-literature

LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-03-12 | GSE109493 | GEO

LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (RNA-Seq)

Project description:Transcriptome analysis by high throughput sequencing

2018-03-12 | GSE109491 | GEO

LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia

Project description:LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia

| PRJNA431204 | ENA

LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (ChIP-Seq)

Project description:LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (ChIP-Seq)

| PRJNA431217 | ENA

LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (RNA-Seq)

Project description:LKB1, Salt-Inducible Kinases, and MEF2C are linked dependencies in acute myeloid leukemia (RNA-Seq)

| PRJNA431335 | ENA

LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription.

Project description:BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Treatment options are limited and prophylactic agents are not available. We have previously demonstrated an essential role for CREB-regulating transcriptional coactivators (CRTCs) in HTLV-1 transcription.ResultsIn this study we report on the negative regulatory role of LKB1 tumor suppressor and salt-inducible kinases (SIKs) in the activation of HTLV-1 long terminal repeats (LTR) by the oncoprotein Tax. Activation of LKB1 and SIKs effectively blunted Tax activity in a phosphorylation-dependent manner, whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function. Activated LKB1 and SIKs associated with Tax and suppressed Tax-induced LTR activation by counteracting CRTCs and CREB. Enforced expression of LKB1 or SIK1 in cells transfected with HTLV-1 molecular clone pX1MT repressed proviral transcription. On the contrary, depletion of LKB1 in pX1MT-transfected cells and in HTLV-1-transformed T cells boosted the expression of Tax. Treatment of HTLV-1 transformed cells with metformin led to LKB1/SIK1 activation, reduction in Tax expression, and inhibition of cell proliferation.ConclusionsOur findings revealed a new function of LKB1 and SIKs as negative regulators of HTLV-1 transcription. Pharmaceutical activation of LKB1 and SIKs might be considered as a new strategy in anti-HTLV-1 and anti-ATL therapy.

| S-EPMC3640950 | biostudies-literature

Chemical Inhibition of Salt-Inducible Kinase as Therapeutic Strategy in Acute Myeloid Leukemia [ChIP-Seq]

Project description:Genome-wide binding/occupancy profiling by high throughput sequencing

2019-11-01 | GSE129861 | GEO

Salt-inducible kinase inhibition suppresses acute myeloid leukemia progression in vivo.

Project description:Lineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a salt-inducible kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF myocyte enhancer factor (MEF2C). In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C. In this study, we evaluated whether inhibition of SIK3 with the tool compound YKL-05-099 can suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells under in vitro and in vivo conditions. Similar phenotypes were obtained when cells were exposed to YKL-05-099, which caused cell-cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. Using a gatekeeper allele of SIK3, we found that the antiproliferative effects of YKL-05-099 occurred through on-target inhibition of SIK3 kinase activity. Based on these findings, we treated 2 different mouse models of MLL-AF9 AML with YKL-05-099, which attenuated disease progression in vivo and extended animal survival at well-tolerated doses. These findings validate SIK3 as a therapeutic target in MEF2C-addicted AML and provide a rationale for developing druglike inhibitors of SIK3 for definitive preclinical investigation and for studies in human patients.

| S-EPMC6940199 | biostudies-literature

Roles of salt‑inducible kinases in cancer (Review).

Project description:Salt inducible kinases (SIKs) with three subtypes SIK1, SIK2 and SIK3, belong to the AMP‑activated protein kinase family. They are expressed ubiquitously in humans. Under normal circumstances, SIK1 regulates adrenocortical function in response to high salt or adrenocorticotropic hormone stimulation, SIK2 is involved in cell metabolism, controlling insulin signaling and gluconeogenesis and SIK3 coordinates with the mTOR complex, promoting cancer. The dysregulation of SIKs has been widely detected in various types of cancers. Based on most of the existing studies, SIK1 is mostly considered a tumor inhibitor, SIK2 and SIK3 are usually associated with tumor promotion. However, the functions of SIKs have shown contradictory in certain tumors, suggesting that SIKs cannot be simply classified as oncogenes or tumor suppressor genes. The present review provided a comprehensive summary of the roles of SIKs in the initiation and progression of different cancers, aiming to elucidate their clinical value and discuss potential strategies for targeting SIKs in cancer therapy.

| S-EPMC10546379 | biostudies-literature

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