KAT7 suppresses tumorigenesis in clear cell renal cell carcinoma (ccRCC) by regulating cell cycle and ferroptosis sensitivity.

Clear cell renal cell carcinoma (ccRCC) is one of the most aggressive malignancies in the urological system, known for its high immunogenicity. However, its pathogenesis remains unclear. This study utilized bioinformatics algorithms and in vitro experiments to investigate the role of KAT7 in ccRCC. The results indicate that KAT7 is significantly downregulated in ccRCC tissues and cell lines, which is linked to distant metastasis and unfavorable outcomes in ccRCC patients. Overexpression of KAT7 in vitro notably decreased the proliferation, migration, and invasion of renal cancer cells and inhibited Epithelial-Mesenchymal Transition (EMT). Additionally, Gene Set Enrichment Analysis (GSEA) demonstrated that KAT7-related gene functions are associated with cell cycle and ferroptosis transcription factors. Treatment with a KAT7 acetylation inhibitor in ccRCC cell lines reversed the S phase arrest caused by KAT7 overexpression. Similarly, ferroptosis inhibitors alleviated ferroptosis induced by overexpressed KAT7. In conclusion, the findings suggest that KAT7 acts as a tumor suppressor in ccRCC by modulating the cell cycle and ferroptosis sensitivity, underscoring its potential as a therapeutic target and prognostic biomarker for renal cell carcinoma patients.

KAT7 serves as an oncogenic gene and regulates CCL3 expression via STAT1 signaling in osteosarcoma.

Osteosarcoma, considered as the primary cause of malignant bone tumors in children, necessitates novel therapeutic strategies to enhance overall survival rates. KAT7, a histone acetyltransferase, exerts pivotal functions in gene transcription and immune modulation. In light of this, our study identified a significant upregulation of KAT7 in the mRNA and protein levels in human osteosarcoma, boosting cell proliferation in vivo and in vitro. In addition, KAT7-mediated H3K14ac activation induced MMP14 transcription, leading to increased expression and facilitation of osteosarcoma cell metastasis. Subsequent bioinformatics analyses highlighted a correlation between KAT7 and adaptive immune responses, indicating CCL3 as a downstream target of KAT7. Mechanistically, STAT1 was found to transcriptionally upregulate CCL3 expression. Furthermore, overexpression of KAT7 suppressed CCL3 secretions, whereas knockdown of KAT7 enhanced its release. Overall, these findings underscore the oncogenic role of KAT7 in regulating immune responses for osteosarcoma treatment.

The histone acetyltransferase HBO1 promotes efficient tip cell sprouting during angiogenesis.

Blood vessel growth and remodelling are essential during embryonic development and disease pathogenesis. The diversity of endothelial cells (ECs) is transcriptionally evident and ECs undergo dynamic changes in gene expression during vessel growth and remodelling. Here, we investigated the role of the histone acetyltransferase HBO1 (KAT7), which is important for activating genes during development and for histone H3 lysine 14 acetylation (H3K14ac). Loss of HBO1 and H3K14ac impaired developmental sprouting angiogenesis and reduced pathological EC overgrowth in the retinal endothelium. Single-cell RNA sequencing of retinal ECs revealed an increased abundance of tip cells in Hbo1-deficient retinas, which led to EC overcrowding in the retinal sprouting front and prevented efficient tip cell migration. We found that H3K14ac was highly abundant in the endothelial genome in both intra- and intergenic regions, suggesting that HBO1 acts as a genome organiser that promotes efficient tip cell behaviour necessary for sprouting angiogenesis. This article has an associated 'The people behind the papers' interview.

Anti-aging effect of ß-carotene through regulating the KAT7-P15 signaling axis, inflammation and oxidative stress process.

BACKGROUND: Research on aging is growing as the elderly make up a greater share of the population, focusing on reversing and inhibiting the aging process. The exhaustion and senescence of stem cells are the fundamental drivers behind aging. ß-Carotene has been depicted to have many biological functions, and we speculate that it may have an anti-aging effect. METHODS: Firstly, the anti-aging property of ß-carotene was investigated in vitro using mesenchymal stem cells (MSCs) induced by H2O2. The anti-aging effect was characterized using Western-bloting, confocal laser scanning microscopy, indirect immunofluorescence, and immunohistochemistry. The anti-aging property was also tested in vivo using aged mice. RESULTS: The in vitro experiment revealed that ß-carotene could relieve the aging of MSCs, as evidenced by a series of aging marker molecules such as p16 and p21. ß-Carotene appeared to inhibit aging by regulating the KAT7-P15 signaling axis. The in vivo experiment revealed that ß-carotene treatment has significantly down-regulated the aging level of tissues and organs. CONCLUSIONS: In this work, we explored the anti-aging effect of ß-carotene in vivo and in vitro. The experimental results indicate that ß-carotene may be an important potential anti-aging molecule, which can be used as a drug or in functional food to treat aging in the future.

MEAF6 is essential for cell proliferation and plays a role in the assembly of KAT7 complexes.

Myst family genes encode lysine acetyltransferases that mainly mediate histone acetylation to control transcription, DNA replication and DNA damage response. They form tetrameric complexes with PHD-finger proteins (Brpfs or Jades) and small non-catalytic subunits Ing4/5 and Meaf6. Although all the components of the complex are well-conserved from yeast to mammals, the function of Meaf6 and its homologs has not been elucidated in any species. Here we revealed the role of Meaf6 utilizing inducible Meaf6 KO ES cells. By elimination of Meaf6, proliferation ceased although histone acetylations were largely unaffected. In the absence of Meaf6, one of the Myst family members Myst2/Kat7 increased the ability to interact with PHD-finger proteins. This study is the first indication of the function of Meaf6, which shows it is not essential for HAT activity but modulates the assembly of the Kat7 complex.

A novel long non-coding RNA-KAT7 is low expressed in colorectal cancer and acts as a tumor suppressor.

BACKGROUND: The abnormal expression of many long non-coding RNAs (lncRNAs) has been reported in the progression of various tumors. However, the potential biological roles and regulatory mechanisms of long non-coding RNAs in the development of colorectal cancer (CRC) have not yet been fully elucidated. Therefore, it is crucial to identify that lncRNAs can be used for the clinical prevention and treatment of CRC. METHODS: In our previous work, we identificated a novel lncRNA, lncRNA-KAT7, and found that the expression of lncRNA-KAT7 in CRC tissues was significantly lower than that in matched normal intestinal tissues, and the expression in CRC cell lines was lower than that of normal intestinal epithelial cells (P < 0.05). Besides, the expression of lncRNA-KAT7 is negative associated with age, tumor size, tumor differentiation, lymph node metastasis of CRC patients. The potential biological effects and molecular mechanisms of lncRNA-KAT7 in CRC were evaluated using a series of CCK-8 assay, clone formation assay, EdU proliferation assay, scratch determination, transwell determination, western blot analysis, and nude subcutaneous tumorigenesis model construction cell and animal experiments. RESULTS: The expression of lncRNA-KAT7 in CRC tissues was lower than that in matched normal tissues and normal intestinal epithelial cells (P < 0.05). Decreased expression of lncRNA-KAT7 is associated with clinicopathological features of poor CRC patients. In vitro experiments showed that up-regulation of lncRNA-KAT7 expression in CRC cells inhibited cell proliferation and migration. In vivo animal experiments showed that the lncRNA-KAT7 also inhibited tumor growth. Western blot analysis showed that the expression of lncRNA-KAT7 was up-regulated in HCT116 cells, the expression of E-cadherin increased, and the expression of Vimentin, MMP-2 and ß-catenin protein was down-regulated so did the phosphorylation NF-κB P65. The results confirm that the expression of lncRAN-KAT7 can inhibit the malignant phenotype of CRC cells. CONCLUSIONS: Up to now, as a novel lncRNA, lncRNA-KAT7 has not any relevant research and reports. The results confirm that the expression of lncRNA-KAT7 can inhibit the malignant phenotype of CRC cells. And it can be used as a new diagnostic biomarker and therapeutic target for the development of CRC.

Upregulated KAT7 in synovial fibroblasts promotes Th17 cell differentiation and infiltration in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease involving multiple cellular participants, of which synovial fibroblasts (SFs) are tightly connected with the development and progression of RA. Here, we provide evidence confirming that KAT7, an H4-specific histone acetylase, is upregulated in SFs of RA patients, which is at least attributed to the stimulation by RA-associated proinflammatory cytokines, such as TNF-α, IL-1ß or IFN-γ. In addition, KAT7 overexpression in cultured human fibroblast-like synoviocytes (HFLSs) induces IL-6 and TGF-ß expression through an epigenetic mechanism, and in vitro T helper 17 (Th17) cell polarization cultured in these supernatants shows promoted cell differentiation. Moreover, KAT7 overexpression in HFLSs induces CCL20 expression via p44/42 MAPK pathway, whereby promoting Th17 cell migration. These two activities of KAT7 in RA SFs indicate its potential roles in accelerating RA pathology. Overall, these results demonstrate some connections between KAT7 upregulated in RA SFs and RA progression and present the inhibition of KAT7 activity as a novel therapeutic target for interfering RA disease.

KAT7 enhances the proliferation and metastasis of head and neck squamous carcinoma by promoting the acetylation level of LDHA.

Lysine acetyltransferase 7 (KAT7), a histone acetyltransferase, has recently been identified as an oncoprotein and has been implicated in the development of various malignancies. However, its specific role in head and neck squamous carcinoma (HNSCC) has not been fully elucidated. Our study revealed that high expression of KAT7 in HNSCC patients is associated with poor survival prognosis and silencing KAT7 inhibits the Warburg effect, leading to reduced proliferation, invasion, and metastatic potential of HNSCC. Further investigation uncovered a link between the high expression of KAT7 in HNSCC and tumor-specific glycolytic metabolism. Notably, KAT7 positively regulates Lactate dehydrogenase A (LDHA), a key enzyme in metabolism, to promote lactate production and create a conducive environment for tumor proliferation and metastasis. Additionally, KAT7 enhances LDHA activity and upregulates LDHA protein expression by acetylating the lysine 118 site of LDHA. Treatment with WM3835, a KAT7 inhibitor, effectively suppressed the growth of subcutaneously implanted HNSCC cells in mice. In conclusion, our findings suggest that KAT7 exerts pro-cancer effects in HNSCC by acetylating LDHA and may serve as a potential therapeutic target. Inhibiting KAT7 or LDHA expression holds promise as a therapeutic strategy to suppress the growth and progression of HNSCC.

Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy.

Lysine acetyltransferases (KATs) are a family of epigenetic enzymes involved in the regulation of gene expression; they represent a promising class of emerging drug targets. The frequent molecular dysregulation of these enzymes, as well as their mechanistic links to biological functions that are crucial to cancer, have led to exploration around the development of small-molecule inhibitors against KATs. Despite early challenges, recent advances have led to the development of potent and selective enzymatic and bromodomain (BRD) KAT inhibitors. In this review we discuss the discovery and development of new KAT inhibitors and their application as oncology therapeutics. Additionally, new chemically induced proximity approaches are presented, offering opportunities for unique target selectivity profiles and tissue-specific targeting of KATs. Emerging clinical data for CREB binding protein (CREBBP)/EP300 BRD inhibitors and KAT6 catalytic inhibitors indicate the promise of this target class in cancer therapeutics.

KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer's disease.

BACKGROUND: Epidemiological studies have revealed a correlation between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D). Insulin resistance in the brain is a common feature in patients with T2D and AD. KAT7 is a histone acetyltransferase that participates in the modulation of various genes. AIM: To determine the effects of KAT7 on insulin patients with AD. METHODS: APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes, respectively. An in vitro model of AD was established by Aß stimulation. Insulin resistance was induced by chronic stimulation with high insulin levels. The expression of microtubule-associated protein 2 (MAP2) was assessed using immunofluorescence. The protein levels of MAP2, Aß, dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), IRS-1, p-AKT, total AKT, p-GSK3ß, total GSK3ß, DYRK1A, and KAT7 were measured via western blotting. Accumulation of reactive oxygen species (ROS), malondialdehyde (MDA), and SOD activity was measured to determine cellular oxidative stress. Flow cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation, respectively. Relative RNA levels of KAT7 and DYRK1A were examined using quantitative PCR. A chromatin immunoprecipitation assay was conducted to detect H3K14ac in DYRK1A. RESULTS: KAT7 expression was suppressed in the AD mice. Overexpression of KAT7 decreased Aß accumulation and MAP2 expression in AD brains. KAT7 overexpression decreased ROS and MDA levels, elevated SOD activity in brain tissues and neurons, and simultaneously suppressed neuronal apoptosis. KAT7 upregulated levels of p-AKT and p-GSK3ß to alleviate insulin resistance, along with elevated expression of DYRK1A. KAT7 depletion suppressed DYRK1A expression and impaired H3K14ac of DYRK1A. HMGN1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 depletion. CONCLUSION: We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylation. Our findings suggest that KAT7 is a novel and promising therapeutic target for the resistance in AD.

Circ-myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia-Inducible Factor-1α Expression.

Background Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of pulmonary hypertension (PH). Hypoxia-inducible factor (HIF) is a well-known modulator of hypoxia-induced PH. The role and underlying mechanism of circRNAs in the regulation of HIF expression remains elusive. Methods and Results We profiled pulmonary artery transcriptomes using RNA sequencing and screened circRNAs associated with hypoxia treatment. The expression of a novel circRNA, circ_chr11_67292179-67294612 (circ-myh8), was increased by hypoxia in a time-dependent manner. We evaluated the effects of circ-myh8 overexpression by adeno-associated virus or inhibition by short hairpin RNA on proliferation and cell cycling in mice and pulmonary artery smooth muscle cells. Overexpression of circ-myh8 promotes PH under normoxia, and disruption of circ-myh8 by short hairpin RNA mitigates PH in chronic hypoxic mice. Biologically, circ-myh8 induces the proliferation and cell-cycle progression of pulmonary artery smooth muscle cells in vivo and in vitro. Mechanistically, RNA pull-down and RNA immunoprecipitation assays were used to examine the interaction of circRNAs with the binding protein KAT7 (lysine acetyltransferase 7). The acetylation level of lysine 5 of histone H4 in the transcriptional initiation region of HIF1α was determined by chromatin immunoprecipitation assay followed by reverse transcription-quantitative polymerase chain reaction. Circ-myh8 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of HIF1α, which elicits acetylation of lysine 5 of histone H4 in their promoters. Conclusions Our findings not only reveal the pivotal roles of circ-myh8 in governing histone modification in anti-PH treatment but also advocate triggering the circ-myh8/KAT7/HIF1α pathway to combat PH.

Effect of sitagliptin on down-regulation of KAT7 and SIRT1 gene expression in breast cancer cell line MCF7.

BACKGROUND: To date, the main clinical interest in DPP4 is focused on its inhibition in diabetic patients to prolong the half-life of incretins. Epigenetic alterations resulting from DPP4 inhibition have been poorly explored. OBJECTIVE: The objective of this study was to determine, whether sitagliptin, a DPP4 inhibitor, has effects on the expression of KAT7 and SIRT1 (genes encoding a histone acetyltransferase and a histone deacetylase, respectively) in MCF7 breast cancer cells, which play an essential role in modulating the epigenetic landscape of chromatin. MATERIAL AND METHODS: MCF7 cells were incubated for 20 h with sitagliptin at concentrations of 0.5, 1.0 and 2.0 µM. Total RNA was isolated and the relative mRNA expression of KAT7 and SIRT1 was determined by RT-qPCR. RESULTS: There was downregulation in the relative expression of both genes; for KAT7, downregulation reached up to 0.49 (p = 0.027) and for SIRT1, it reached up to 0.55 (p = 0.037). CONCLUSIONS: These results suggest that sitagliptin has effects on the histone epigenetic landscape. This topic deserves further study due to the current sample use of DPP4 inhibitors in diabetic patients.

ANTECEDENTES: Hasta la fecha, el principal interés clínico de la DPP4 se centra en su inhibición en pacientes diabéticos para prolongar la vida media de las incretinas. Las alteraciones epigenéticas resultantes de la inhibición de DPP4 han sido poco exploradas. OBJETIVO: Determinar si la sitagliptina, un inhibidor de DPP4, tiene efectos sobre la expresión de KAT7 y SIRT1 (genes que codifican una histona acetiltransferasa y una histona desacetilasa, respectivamente) en células de cáncer de mama MCF7, que desempeñan un papel esencial en la modulación del paisaje epigenético de la cromatina. MÉTODO: Las células MCF7 se incubaron durante 20 h con sitagliptina a concentraciones de 0.5, 1.0 y 2.0 µM. Se aisló el ARN total y se determinó la expresión relativa de ARNm de KAT7 y SIRT1 mediante RT-qPCR. RESULTADOS: Hubo una regulación a la baja en la expresión relativa de ambos genes; para KAT7, la regulación negativa alcanzó hasta 0.49 (p = 0.027) y para SIRT1 alcanzó hasta 0.55 (p = 0.037). CONCLUSIONES: Estos resultados sugieren que la sitagliptina tiene efectos sobre el paisaje epigenético de las histonas. Este tema merece más estudios debido al uso actual de inhibidores de DPP4 en pacientes diabéticos.

The chromatin reader protein ING5 is required for normal hematopoietic cell numbers in the fetal liver.

ING5 is a component of KAT6A and KAT7 histone lysine acetylation protein complexes. ING5 contains a PHD domain that binds to histone H3 lysine 4 when it is trimethylated, and so functions as a 'reader' and adaptor protein. KAT6A and KAT7 function are critical for normal hematopoiesis. To examine the function of ING5 in hematopoiesis, we generated a null allele of Ing5. Mice lacking ING5 during development had decreased foetal liver cellularity, decreased numbers of hematopoietic stem cells and perturbed erythropoiesis compared to wild-type control mice. Ing5-/- pups had hypoplastic spleens. Competitive transplantation experiments using foetal liver hematopoietic cells showed that there was no defect in long-term repopulating capacity of stem cells lacking ING5, suggesting that the defects during the foetal stage were not cell intrinsic. Together, these results suggest that ING5 function is dispensable for normal hematopoiesis but may be required for timely foetal hematopoiesis in a cell-extrinsic manner.

KAT7 promotes radioresistance through upregulating PI3K/AKT signaling in breast cancer.

Chromatin-modifying enzymes are commonly altered in cancers, but the molecular mechanism by which they regulate cancers remains poorly understood. Herein, we demonstrated that Lysine acetyltransferase 7 (KAT7) was upregulated in breast cancer. KAT7 expression negatively correlated with the survival of breast cancer patients, and KAT7 silencing suppressed breast cancer radioresistance in vitro. Mechanistically, KAT7 activated Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) transcription, leading to enhanced PI3K/AKT signaling and radioresistance. Overexpression of AKT or PIK3CA restored radioresistance suppression induced by KAT7 inhibition. Moreover, overexpression of KAT7, but not KAT7 acetyltransferase activity-deficient mutants promoted AKT phosphorylation at the Ser473 site, PIK3CA expression and radioresistance suppression due to KAT7 inhibition. In conclusion, KAT7 has huge prospects for clinical application as a new target for predicting radioresistance in breast cancer patients.

Stem cell plasticity, acetylation of H3K14, and de novo gene activation rely on KAT7.

In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we find that KAT7 and H3K14ac are present not only at transcribed genes but also at inactive genes, intergenic regions, and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7 but indispensable for the activation of repressed genes. The absence of KAT7 abrogates neural stem cell plasticity, diverse differentiation pathways, and cerebral cortex development. Re-expression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation.

Insulin sensitivity in the aged heart is improved by down-regulation of KAT7 in vivo and in vitro.

Insulin has an important regulatory effect on the heart, and the important regulatory effect of insulin on the heart is the regulation of substrate utilization. Studies have shown that aging is closely related to insulin resistance, and aging is thought to be one of the underlying causes of insulin resistance. Additionally, chronic inflammation is a major risk factor for aging and aging-related diseases. How to delay or reverse insulin resistance caused by aging is an important scientific problem. In the current study, we used cardiomyocyte cell lines and isolated heart cells as an in vitro model, and aged mice as in vivo model to study the effect of KAT7 on insulin resistance, and results showed that knockdown or inhibiting KAT7 can significantly increase the insulin sensitivity in vivo and in vitro. In addition, the knockdown of KAT7 could reduce inflammation and oxidative stress caused by aging. These findings indicate that KAT7 can be used as one of the potential targets for the treatment of insulin resistance caused by aging.

KAT7 promoted gastric cancer progression through promoting YAP1 activation.

Lysine acetyltransferase 7 (KAT7) was upregulated in gastric cancer (GC) patient tissues, and associated with poor prognosis and metastasis. However, its specific role in GC remains unclear. This study aimed to annotate the role of KAT7 in GC cells. The results showed that the overexpression of KAT7 promoted cell growth, migration, and invasion, while KAT7 inhibition has the opposite effect. Besides, KAT7 participated in cell cycle phase distribution and epithelial-mesenchymal transition (EMT) process of GC cells. In addition, KAT7 promoted the transcription and nuclear translocation of Yes-associated protein 1 (YAP1) in MKN45 cells. Silence of YAP1 partly reversed the promoting effect of KAT7 on GC cells progression. In summary, this study indicates that KAT7 promoted GC cells progression through promoting YAP1 activation, contributes to understand the specific role of KAT7 in GC.

KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity.

Amino acids play crucial roles in the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) pathway. However, the underlying mechanisms are not fully understood. Here, we establish a cell-free system to mimic the activation of MTORC1, by which we identify CANX (calnexin) as an essential regulator for leucine-stimulated MTORC1 pathway. CANX translocates to lysosomes after leucine deprivation, and its loss of function renders either the MTORC1 activity or the lysosomal translocation of MTOR insensitive to leucine deprivation. We further find that CANX binds to LAMP2 (lysosomal associated membrane protein 2), and LAMP2 is required for leucine deprivation-induced CANX interaction with the Ragulator to inhibit Ragulator activity toward RRAG GTPases. Moreover, leucine deprivation promotes the lysine (K) 525 crotonylation of CANX, which is another essential condition for the lysosomal translocation of CANX. Finally, we find that KAT7 (lysine acetyltransferase 7) mediates the K525 crotonylation of CANX. Loss of KAT7 renders the MTORC1 insensitivity to leucine deprivation. Our findings provide new insights for the regulatory mechanism of the leucine-stimulated MTORC1 pathway.Abbreviations: CALR: calreticulin; CANX: calnexin; CLF: crude lysosome fraction; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; ER: endoplasmic reticulum; GST: glutathione S-transferase; HA: hemagglutinin; HEK293T: human embryonic kidney-293T; KAT7: lysine acetyltransferase 7; Kcr; lysine crotonylation; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LAMTOR/Ragulator: late endosomal/lysosomal adaptor: MAPK and MTOR activator; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PDI: protein disulfide isomerase; PTM: post-translational modification; RPS6KB1/p70S6 kinase 1: ribosomal protein S6 kinase B1; RPTOR: regulatory associated protein of MTOR complex 1; SESN2: sestrin 2; TMEM192: transmembrane protein 192; ULK1: unc-51 like autophagy activating kinase 1.

Circular RNA Foxo3 Relieves Myocardial Ischemia/Reperfusion Injury by Suppressing Autophagy via Inhibiting HMGB1 by Repressing KAT7 in Myocardial Infarction.

INTRODUCTION: Myocardial infarction is coronary artery-related heart disease, and the leading cause of mortality globally. Circular RNAs (circRNAs) are a new type of regulatory RNAs and participate in multiple pathological cardiac progression. METHODS: However, the function of circFoxo3 in MI-induced myocardial injury remains obscure. RESULTS: Significantly, we identified that circFoxo3 was downregulated in the MI rat model and the overexpression of circFoxo3 ameliorated MI-induced cardiac dysfunction and attenuated MI-induced autophagy in rat model. Meanwhile, the overexpression of circFoxo3 repressed oxygen-glucose deprivation (OGD)-induced autophagy, apoptosis, inflammation, and injury of cardiomyocyte in vitro. Mechanically, we identified that the expression of KAT7 was reduced by circFoxo3 overexpression in cardiomyocytes. Meanwhile, the expression of HMGB1 was repressed by the depletion of KAT7 in cardiomyocytes. The enrichment of histone H3 lysine 14 acetylation (H3K14ac) and RNA polymerase II (RNA pol II) on HMGB1 promoter was inhibited by the knockdown of KAT7. Moreover, the overexpression of circFoxo3 suppressed HMGB1 expression and KAT7 overexpression rescued the expression of HMGB1 in cardiomyocytes. The enrichment of KAT7, H3K14ac, and RNA poly II on HMGB1 promoter was decreased by circFoxo3 overexpression, while the overexpression of KAT7 could reverse the effect. The overexpression of KAT7 or HMGB1 could reverse circFoxo3-attenuated cardiomyocyte injury and autophagy in vitro. Thus, we conclude that circular RNA circFoxo3 relieved myocardial ischemia/reperfusion injury by suppressing autophagy via inhibiting HMGB1 by repressing KAT7 in MI. DISCUSSION: Our finding provides new insight into the mechanism by which circFoxo3 regulates MI-related cardiac dysfunction by targeting KAT7/HMGB1 axis.

LncRNA-KAT7 Negatively Regulates miR-10a Through an Epigenetic Pathway to Participate in Nonsmall Cell Lung Cancer.

Objective: LncRNA-KAT7 is a recently identified tumor suppressor in colorectal cancer, whereas its roles in other malignancies remain unclear. This study aimed to investigate the roles of KAT7 in nonsmall cell lung cancer (NSCLC). Results: The results showed that KAT7 was downregulated in NSCLC and predicted poor survival. KAT7 negatively correlated with miR-10a in NSCLC. In NSCLC cells, overexpression of KAT7 led to downregulated miR-10a, whereas silencing of KAT7 led to upregulated miR-10a. Methylation-specific polymerase chain reaction revealed that KAT7 positively regulated the methylation of miR-10a. Cell proliferation assay showed that overexpression of miR-10a led to increased proliferation rate of NSCLC cells. In addition, overexpression of KAT7 played an opposite role and reduced the effects of the overexpression of miR-10a. Conclusion: In conclusion, KAT7 negatively regulates miR-10a through epigenetic mechanisms to participate in NSCLC cell proliferation.