Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding

Lv, Deguan; Feng, Jia; Hou, Yanli; Sang, Youzhou; Alvarez, Angel A.; Zhang, Weiwei; Gao, Wei; Hu, Bo; Cheng, Shi Yuan; Ge, Jian; Li, Yanxin; Feng, Haizhong

doi:10.1158/0008-5472.can-17-1388

Cited by 76 publications

(63 citation statements)

References 41 publications

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“…Both of the genes that were altered in only the PE/CA-PJ49 Ctx R 1 cells, KAT6A and NSD1 ( Table 2), are involved in epigenetic regulation of gene expression. KAT6A encodes lysine acetyltransferase 6A (KAT6A), a histone acetyltransferase [45,46]. The specific alteration identified in this analysis (p.1228_1228del) has not been reported; thus, its impact on KAT6A protein expression and function are unknown.…”

Section: Discussionmentioning

confidence: 86%

“…The specific alteration identified in this analysis (p.1228_1228del) has not been reported; thus, its impact on KAT6A protein expression and function are unknown. However, KAT6A mRNA levels are increased in glioblastoma samples compared to normal brain tissue, and KAT6A and has been shown to promote glioma cell proliferation via upregulation of PIK3CA expression and subsequent activation of PI3K/Akt signaling [45]. Thus, if the mutation identified in the Ctx R 1 cells is an activating mutation, this KAT6A alteration could promote cetuximab resistance by activating PI3K/Akt signaling, a previously identified mediator of cetuximab resistance [3,14,22,26].…”

Section: Discussionmentioning

confidence: 98%

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Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

et al. 2020

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The epidermal growth factor receptor inhibitor cetuximab is the only oncogene-targeted agent that has been FDA approved for the treatment of head and neck squamous cell carcinoma (HNSCC). Currently, there are no biomarkers used in the clinic to predict which HNSCC tumors will respond to cetuximab, and even in tumors that regress with treatment, acquired resistance occurs in the majority of cases. Though a number of mechanisms of acquired resistance to cetuximab have been identified in preclinical studies, no therapies targeting these resistance pathways have yet been effectively translated into the clinic. To address this unmet need, we examined the role of the cytokine interleukin 6 (IL-6) in acquired cetuximab resistance in preclinical models of HNSCC. We found that IL-6 secretion was increased in PE/CA-PJ49 cells that had acquired resistance to cetuximab compared to the parental cells from which they were derived. However, addition of exogenous IL-6 to parental cells did not promote cetuximab resistance, and inhibition of the IL-6 pathway did not restore cetuximab sensitivity in the cetuximab-resistant cells. Further examination of the IL-6 pathway revealed that expression of IL6R, which encodes a component of the IL-6 receptor, was decreased in cetuximab-resistant cells compared to parental cells, and that treatment of the cetuximab-resistant cells with exogenous IL-6 did not induce phosphorylation of signal transducer and activator of transcription 3, suggesting that the IL-6 pathway was functionally impaired in the cetuximab-resistant cells. These findings demonstrate that, even if IL-6 is increased in the context of cetuximab resistance, it is not necessarily required for maintenance of the resistant phenotype, and that targeting the IL-6 pathway may not restore sensitivity to cetuximab in cetuximab-refractory HNSCC.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 98%

Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

et al. 2020

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“…In cells, shRNA KD shRNA KD of KAT6A in U87 and LN229 cells, reduced H3K23ac and to a lesser degree H3K9ac and H3K14ac [43] www.advancedsciencenews.com www.bioessays-journal.com levels has not been reported for Kat6a null cells to date. No histone acetylation target has been attributed to KAT6B at this point.…”

Section: H3k14 Indirect Evidence Via Ing5 In Cellsmentioning

confidence: 88%

“…[40,41] Alternatively, the reduction in H3K9ac may be secondary to a yet to be discovered genome-wide histone lysine target of KAT6A. [42,43] Assessment of H3K23 acetylation www.advancedsciencenews.com www.bioessays-journal.com [19] CBP P300 [42,43] Assessment of H3K23 acetylation www.advancedsciencenews.com www.bioessays-journal.com [19] CBP P300…”

Section: Broad or Histone Lysine Residue-specific Hat Activity?mentioning

confidence: 99%

Histone Lysine and Genomic Targets of Histone Acetyltransferases in Mammals

Voss

Thomas

2018

BioEssays

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Histone acetylation has been recognized as an important post-translational modification of core nucleosomal histones that changes access to the chromatin to allow gene transcription, DNA replication, and repair. Histone acetyltransferases were initially identified as co-activators that link DNA-binding transcription factors to the general transcriptional machinery. Over the years, more chromatin-binding modes have been discovered suggesting direct interaction of histone acetyltransferases and their protein complex partners with histone proteins. While much progress has been made in characterizing histone acetyltransferase complexes biochemically, cell-free activity assay results are often at odds with in-cell histone acetyltransferase activities. In-cell studies suggest specific histone lysine targets, but broad recruitment modes, apparently not relying on specific DNA sequences, but on chromatin of a specific functional state. Here we review the evidence for general versus specific roles of individual nuclear lysine acetyltransferases in light of in vivo and in vitro data in the mammalian system.

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“…Histone acetylation levels are often correlated with glioma progression (R. Huang et al, ; J. V. Lee et al, ). HAT KAT6A acetylates histone 3 at K23 and recruits the nuclear receptor binding protein TRIM24 to activate the transcription of PIK3CA , thereby promoting PI3K/AKT signaling and GBM progression (Lv et al, ). KAT6A silencing suppresses cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system (Lv et al, ).…”

Section: Epigenetic Regulation In Glioblastomamentioning

confidence: 99%

Developmental origins and oncogenic pathways in malignant brain tumors

Qian

Zhou

2019

WIREs Developmental Biology

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Brain tumors such as adult glioblastomas and pediatric high-grade gliomas or medulloblastomas are among the leading causes of cancer-related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single-cell resolution have shed new light onto diverse tumor-driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high-grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage-specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high-grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors.

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Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding

Cited by 76 publications

References 41 publications

Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance

Histone Lysine and Genomic Targets of Histone Acetyltransferases in Mammals

Developmental origins and oncogenic pathways in malignant brain tumors

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