The lysine methyltransferase SMYD2 facilitates neointimal hyperplasia by regulating the HDAC3-SRF axis

Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary heart disease. Here, we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum- and PDGF-BB-induced vascular smooth muscle cells (VSMCs), and in tissues of carotid artery injury-induced neointimal hyperplasia. Smyd2 overexpression in VSMCs (Smyd2-vTg) facilitates, but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown significantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice. Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor (SRF) target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation. HDAC3 directly interacts with and deacetylates SRF, which enhances SRF transcriptional activity in VSMCs. Moreover, SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter. RGFP966, a specific inhibitor of HDAC3, not only counteracts the pro-proliferation effect of SMYD2 overexpression on VSMCs, but also inhibits carotid artery injury-induced neointima formation in mice. HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner. Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.

Sevoflurane inhibits proliferation and invasion of breast cancer cells by promoting SIRT2 expression and inducing ACLY deacetylation / 中华内分泌外科杂志

Objective:To explore the effects of sevoflurane (Sev) on proliferation and invasion of breast cancer cells.Methods:Normal human breast epithelial cell line MCF10A and human breast cancer cell line MCF7 were purchased. The expression level of sirtuin 2 (SIRT2) , ATP citrate lyase (ACLY) in breast cancer cells and acetylation level of ACLY were measured. Breast cancer cells were divided into the following groups: Control group, 2% SEV group, 4% SEV group, si-NC group, si-SIRT2 group, 4% SEV+si-NC group, 4% SEV+si-SIRT2 group, SIRT2 group, SIRT2+ACLY-WT group, SIRT2+ACLY-3KQ group, SIRT2+ACLY-3KQ+4% SEV group, si-ACLY group, si-ACLY+ACLY-WT group, si-ACLY+ACLY-3KQ group. MTT and Transwell assay were used to detect cell proliferation and invasion.Results:Compared with MCF-10A cells (1.00±0.15) , SIRT2 was low expressed in Control group cells (0.43±0.03) ( q=11.98, P<0.001) , SEV could induce the expression of SIRT2 ( F=88.71, P<0.001) . In addition, ACLY and ACLY-3K acetylation level were up-regulated in breast cancer cells (all P<0.05) . Knockdown of SIRT2 or overexpression of ACLY and ACLY-3KQ could promote the proliferation and invasion of MCF7 cells (all P<0.05) , while SEV, overexpression of SIRT2 or knockdown of ACLY showed the opposite effects (all P<0.05) . Conclusion:Sev may inhibit the proliferation and invasion of breast cancer cells through SIRT2, which may be related to the regulation of ACLY deacetylation.

Regulation mechanism of post-translational modification of farnesoid X receptor / 中国临床药理学与治疗学

Farnesoid X receptor (FXR) is a nuclear receptor activated by bile acid that is involved in regulating gene expression related to bile acid, fat, glucose, and amino acid metabolism. The activity of FXR is regulated by a variety of post-translational modifications. Common post-translational modifications of FXR include O-GlcNAcylation, phosphorylation, acetylation, sumoylation, methylation, etc. These post-translational modifications may affect FXR binding of DNA and ligand, heterodimerization, and subcellular localization, and may specifically regulate downstream gene transcription and expression. Different post-translational modifications can lead to changes in FXR stability and biological function, which are closely related to the occurrence of diseases. This paper aims to review the post-translational modification of FXR in the past five years and the mechanisms involved in disease regulation, to explore the effects of post-translational modification on the physiological function of FXR and to provide a theoretical basis for mechanism research targeting FXR.

Role of epigenetic regulation of biological clock genes in tumors / 中国药理学通报

The circadian clock is regulated at the molecular level by transcriptional-translational feedback loop of clock genes, which ensures that a variety of physiological processes have a-round 24 h circadian rhythms, including cell metabolism, cell proliferation, cell apoptosis and tumorigenesis, to maintain the homeostasis. Thus, the disturbance of circadian clock will disrupt homeostasis, causing various diseases, including neoplasm, metabolic syndrome, Parkinson's disease, COPD and cardiovascular diseases. Disturbance of circadian clock is closely related with tumorigenesis, and acts on various molecules and pathways leading to tumorigenesis, including oncogene and tumor suppressor gene, cell cycle, metabolic reprogramming, immune escape, endocrine disruption, alteration of gastrointestinal microbiome. This review focuses on changes in clock genes expression which disrupt cell cycle and may play a role in tumorigenesis, and epi-geneties, an important way to regulate gene expression, which can alter clock gene expression, thus playing an important role in the process of " the alternation of clock gene expression-disruption of cell cycle-tumorigenesis".

Protein phosphorylation involved in psychedelic-induced head-twitch response in rats / 中国药理学通报

Aim To investigate the potential protein post-translational modifications of psychedelic-induced Head-twith response and underling mechanism. Methods Psychedelics LSD, DOM, or Psilocin was administered to rats by intraperitoneal injection to induce head-twitch response, then the most effective dosage was identified to create animal models of head-twitch behavior. Western blot was performed in detecting the protein phosphorylation, acetylation, and ubiquitination in prefrontal cortex of SD rats after 10 min or 30 min injection. Results LSD (0.025 mg • kg~, i. p.), DOM (3 mg•kg

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons. Here we explored how gestational exposure to dexamethasone, a synthetic glucocorticoid commonly used in clinical practice, has lasting effects on offspring's learning and memory. Adult offspring rats of prenatal dexamethasone exposure (PDE) displayed significant impairments in novelty recognition and spatial learning memory, with some phenotypes maintained transgenerationally. PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations, and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory, but these changes failed to carry over to offspring of F5 and F7 generations. Mechanistically, altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission, which might be related to oocyte-specific high expression and transmission of miR-133a-3p. Together, PDE affects hippocampal excitatory synaptic transmission, with lasting consequences across generations, and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

Research progress of histone acetylation in prevention and treatment of heart failure and new ideas based on traditional Chinese medicine / 中国中药杂志

Chronic heart failure(CHF) has become a worldwide public health problem due to its high morbidity and mortality, which seriously endangers people's lifespan and quality of life. In recent years, the treatment strategy of CHF has shifted its emphasis on short-term improvement and transformation of hemodynamics to long-term repair as well as improvement of the biological properties of heart failure. At present, with the continuous deepening of medical research, it has been found that histone acetylation is closely related to the occurrence and development of CHF. Traditional Chinese medicine, via regulating histone acetylation, delays ventricular remodeling, improves energy metabolism, inhibits fibrosis and cardiomyocyte hypertrophy, and intervenes in the development process of heart failure, thus reducing the mortality and the readmission rate and ultimately improving long-term prognosis. Therefore, this study reviewed the mechanism of histone acetylation in the treatment of heart failure as well as its prevention and treatment with traditional Chinese medicine, to provide reference for clinical treatment of CHF.

SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR

Farnesoid X receptor (FXR) is widely accepted as a promising target for various liver diseases; however, panels of ligands in drug development show limited clinical benefits, without a clear mechanism. Here, we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury, which represents the major culprit that limits the clinical benefits of FXR agonists against liver diseases. Upon inflammatory and apoptotic stimulation, enhanced FXR acetylation at K217, closed to the nuclear location signal, blocks its recognition by importin KPNA3, thereby preventing its nuclear import. Concomitantly, reduced phosphorylation at T442 within the nuclear export signals promotes its recognition by exportin CRM1, and thereby facilitating FXR export to the cytosol. Acetylation governs nucleocytoplasmic shuttling of FXR, resulting in enhanced cytosolic retention of FXR that is amenable to degradation by CHIP. SIRT1 activators reduce FXR acetylation and prevent its cytosolic degradation. More importantly, SIRT1 activators synergize with FXR agonists in combating acute and chronic liver injuries. In conclusion, these findings innovate a promising strategy to develop therapeutics against liver diseases by combining SIRT1 activators and FXR agonists.

Hedgehog pathway orchestrates the interplay of histone modifications and tailors combination epigenetic therapies in breast cancer

Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment. However, in human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in breast cancer, especially in triple-negative breast cancer (TNBC). This facilitates the histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in breast cancer promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo breast cancer models including patient-derived TNBC xenograft, we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer. Together, this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.

Research progress in epigenetic pharmacological effects of rhein / 中国中药杂志

Rhein, which is one of the main active components of Rheum palmatum, has a range of pharmacological activities such as the regulation of the metabolism of glucose and lipids, anti-inflammatory, anti-tumor, anti-fibrosis, etc. Epigenetics refers to the heritable variation of gene expression without altering the DNA sequence. It is involved in the emergence and development of inflammation, renal fibrosis, diabetes, cancer, atherosclerosis, and other diseases, thus becoming a new strategy for the treatment of many di-seases. A series of studies have shown that epigenetic modification may be a common molecular mechanism of various pharmacological effects of rhein. This paper summarized the effects of rhein on the regulation of epigenetic modification and its underlying mechanisms, which involve the regulation of DNA methylation, protein acetylation, and RNA methylation, so as to provide a basis for the development and application of rhein.

Knockdown of ACC1 promotes migration of esophageal cancer cell / 中华肿瘤杂志

Objective: To investigate the effect of acetyl-CoA carboxylase 1 (ACC1) knockdown on the migration of esophageal squamous cell carcinoma (ESCC) KYSE-450 cell and underlying mechanism. Methods: Lentiviral transfection was conducted to establish sh-NC control cell and ACC1 knocking down cell (sh-ACC1). Human siRNA HSP27 and control were transfected by Lipo2000 to get si-HSP27 and si-NC. The selective acetyltransferase P300/CBP inhibitor C646 was used to inhibit histone acetylation and DMSO was used as vehicle control. Transwell assay was performed to detect cell migration. The expression of HSP27 mRNA was examined by reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and the expressions of ACC1, H3K9ac, HSP27 and epithelial-mesenchymal transition-related proteins E-cadherin and Vimentin were detected by western blot. Results: The expression level of ACC1 in sh-NC group was higher than that in sh-ACC1 group (P<0.01). The number of cell migration in sh-NC group was (159.00±24.38), lower than (361.80±26.81) in sh-ACC1 group (P<0.01). The protein expression levels of E-cadherin and Vimentin in sh-NC group were statistically significant compared with sh-AAC1 group (P<0.05). The migrated cell number in sh-NC+ si-NC group was (189.20±16.02), lower than (371.60±38.40) in sh-ACC1+ si-NC group (P<0.01). The migrated cell number in sh-NC+ si-NC group was higher than that in sh-NC+ si-HSP27 group (152.40±24.30, P<0.01), and the migrated cell number in sh-ACC1+ si-NC group was higher than that in sh-ACC1+ si-HSP27 group (P<0.01). The protein expression levels of E-cadherin and Vimentin in sh-NC+ si-NC group were significantly different from those in sh-ACC1+ si-NC and sh-NC+ si-HSP27 groups (P<0.01). The protein expression levels of E-cadherin and Vimentin in sh-ACC1+ si-NC group were significantly different from those in sh-ACC1+ si-HSP27 group (P<0.01). After 24 h treatment with C646 at 20 μmmo/L, the migrated cell number in sh-NC+ DMSO group was (190.80±11.95), lower than (395.80±17.10) in sh-ACC1+ DMSO group (P<0.01). The migrated cell number in sh-NC+ DMSO group was lower than that in sh-NC+ C646 group (256.20±23.32, P<0.01). The migrated cell number in sh-ACC1+ DMSO group was higher than that in sh-ACC1+ C646 group (87.80±11.23, P<0.01). The protein expressions of H3K9ac, HSP27, E-cadherin and Vimentin in sh-NC+ DMSO group were significantly different from those in sh-ACC1+ DMSO group and sh-NC+ C646 group (P<0.01). The protein expression levels of H3K9ac, HSP27, E-cadherin and Vimentin in sh-ACC1+ DMSO group were significantly different from those in sh-ACC1+ C646 group (P<0.01). Conclusion: Knockdown of ACC1 promotes the migration of KYSE-450 cell by up-regulating HSP27 and increasing histone acetylation.

Role of acetylation modification of host proteins in tuberculosis / 中华微生物学和免疫学杂志

Post-translational modification of host proteins induced by pathogenic microorganism plays a critical role in the development, treatment and prevention of diseases. Mycobacterium tuberculosis ( Mtb) is an intracellular pathogen that causes tuberculosis. The post-translational modification induced by Mtb infection is essential in the development and progression of tuberculosis. In recent years, it has been found that Mtb-induced host protein acetylation plays an important role in the regulation of host immunity against tuberculosis, which significantly affects the development of tuberculosis. This review focused on the role and mechanism of Mtb in regulating host protein acetylation, aiming to provide reference for future investigation on potential immunotherapy for tuberculosis.

Effects of HDAC6 regulation of HSC70 acetylation level on bone loss in osteoporosis after oophorectomy / 中华内分泌外科杂志

Objective:To investigate the effects of histone deacetylase 6 (histone deacetylase 6, HDAC6) on oopherectomy (OOX) induced osteoporosis (OP) bone loss by binding to the promoter region of heat-shock protein 70 (HSC70) and regulating it’s acetylation.Methods:OP mouse model was established by using OOX methods. Then the mice were divided into sham operation group, OOX group, OOX+shHDAC6 group, OOX+shNC group and OOX+shHDAC6+shHSC70 group. The micro-CT system and Western blot experiment were used to detect the bone microscopic parameters of the mouse right femur and the protein expression levels of osteoblast-specific transcription factors. In vitro experiments, Westwen blot, alkaline phosphatase (ALP) staining and Alizarin Red S (ARS) staining were used to determine the effects of HDAC6 and HSC70 on the osteogenic differentiation of MC3T3-E1 cells. QRT-PCR was used to detect the expression levels of HDAC6 and HSC70 in tissue or cells. The relationship between HDAC6 and HSC70 was analyzed by ChIP experiment.Results:Compared with sham group, the expression of bone mineral density (BMD) , trabecular bone number (Tb. N) , trabecular thickness (Tb.th) and bone volume fraction (BV/TV) in the right femur of OOX group mice were decreased, the expression of TB. Sp was increased, protein expression of OSX and RUNX2 was increased. At the same time, compared with sham group (1±0.11) , the expression of HDAC6 was increased in OOX group (2.33±0.19) ( t=10.56, P<0.001) . Compared with pcDNA3.1-NC group, the protein level of Osterix (OSX) and runt-related transcription factor 2 (RUNX2) , ALP activity and mineralized area in pcDNA3.1-HDAC6 group were decreased (all P<0.05) . ChIP analysis showed that compared with the pcDNA3.1-NC group (5.26±0.47) , the acetylation level of the HSC70 promoter region in the pcDNA3.1-HDAC6 group (2.37±0.21) was significantly reduced ( t=9.72, P<0.001) . Compared with pcDNA3.1-HDAC6 group, the expression of OSX and RUNX2, ALP activity and mineralization were increased in pcDNA3.1-HDAC6+ pcDNA3.1-HSC70 group (all P<0.05) . Compared with OOX+shHDAC6 group, the expression of OSX and RUNX2 protein, BMD, Tb.N, Tb.th and BV/TV were decreased but the expression of Tb. Sp was increased in OOX+ shHDAC6+ shHSC70 group. Conclusions:HDAC6 regulates the acetylation level of HSC70 and then affects OOX-induced OP bone loss. Inhibition of HDAC6 can significantly improve OP bone loss.

Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy

Parkin, an E3 ubiquitin ligase, plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level, but the underlying mechanism is poorly understood. Here, our study demonstrated that inhibition of histone deacetylase (HDAC) by treatment of HDACis activates mitophagy through mediating Parkin acetylation, leading to inhibition of cervical cancer cell proliferation. Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer, indicating the low acetylation level of Parkin. Using mass spectrometry, Parkin is identified to interact with two upstream molecules, acetylase acetyl-CoA acetyltransferase 1 (ACAT1) and deacetylase HDAC2. Under treatment of suberoylanilide hydroxamic acid (SAHA), Parkin is acetylated at lysine residues 129, 220 and 349, located in different domains of Parkin protein. In in vitro experiments, combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1 (PINK1) and the function of Parkin in mitophagy induction and tumor suppression. In tumor xenografts, the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA. Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis, which offers a new mitophagy modulation strategy for cancer therapy.

A network pharmacology-based strategy for predicting the protective mechanism of Ginkgo biloba on damaged retinal ganglion cells / 中国天然药物

Hallmarks of the pathophysiology of glaucoma are oxidative stress and apoptotic death of retinal ganglion cells (RGCs). Ginkgo biloba extract (EGb) with multi-target, multi-pathway functions has been reported to exert positive pharmacological effects on oxidative stress and damaged RGCs. However, the ingredients and anti-apoptotic targets of EGb in the treatment of open-angle glaucoma (OAG) have not been fully elucidated. Therefore, in-depth analysis is necessary for further research. Ginkgo biloba-related and anti-apoptotic targets were identified and then combined to obtain the intersection, representing the potential anti-apoptotic targets of Ginkgo biloba. In addition, compound-anti-apoptotic target and OAG-target protein-protein interaction network were merged to obtain five core genes and compound-OAG-anti-apoptotic target protein-protein interaction network. Consequently, the active compounds and anti-apoptotic targets of Ginkgo biloba in the treatment of OAG were identified, namely luteolin, β-sitosterol, kaempferol, stigmasterol, quercetin, and p53, Bax, Bcl-2, Caspase-3 and Caspase-9, respectively. For the anti-apoptotic targets of Ginkgo biloba in the treatment of OAG, Gene Ontology (GO) and pathway analysis were executed to confirm the gene functions of Ginkgo biloba in antagonizing apoptosis of RGCs. The pathway enrichment was mainly involved in transcriptional activation of p53 responsive genes, activation of caspases and apoptotic processes. Finally, we confirmed the results of the network analysis by H2O2 treated RGC-5 cells in vitro. The results demonstrated that EGb protection can effectively diminish H2O2-induced apoptosis by inhibiting p53 acetylation, reducing the ratio of Bax/Bcl-2 and suppressing the expression of specific cleavage of Caspase-9 and Caspase-3.

Romidepsin (FK228) improves the survival of allogeneic skin grafts through downregulating the production of donor-specific antibody via suppressing the IRE1α-XBP1 pathway / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Antibody-mediated rejection (AMR) is one of the major causes of graft loss after transplantation. Recently, the regulation of B cell differentiation and the prevention of donor-specific antibody (DSA) production have gained increased attention in transplant research. Herein, we established a secondary allogeneic in vivo skin transplant model to study the effects of romidepsin (FK228) on DSA. The survival of grafted skins was monitored daily. The serum levels of DSA and the number of relevant immunocytes in the recipient spleens were evaluated by flow cytometry. Then, we isolated and purified B cells from B6 mouse spleens in vitro by magnetic bead sorting. The B cells were cultured with interleukin-4 (IL-4) and anti-clusters of differentiation 40 (CD40) antibody with or without FK228 treatment. The immunoglobulin G1 (IgG1) and IgM levels in the supernatant were evaluated by enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting were conducted to determine the corresponding levels of messenger RNA (mRNA) and protein expression in cultured cells and the recipient spleens. The results showed that FK228 significantly improved the survival of allogeneic skin grafts. Moreover, FK228 inhibited DSA production in the serum along with the suppression of histone deacetylase 1 (HADC1) and HDAC2 and the upregulation of the acetylation of histones H2A and H3. It also inhibited the differentiation of B cells to plasma cells, decreased the transcription of positive regulatory domain-containing 1 (Prdm1) and X-box-binding protein 1 (Xbp1), and decreased the expression of phosphorylated inositol-requiring enzyme 1 α (p-IRE1α), XBP1, and B lymphocyte-induced maturation protein-1 (Blimp-1). In conclusion, FK228 could decrease the production of antibodies by B cells via inhibition of the IRE1α-XBP1 signaling pathway. Thus, FK228 is considered as a promising therapeutic agent for the clinical treatment of AMR.

Emerging role of protein modification in inflammatory bowel disease / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The onset of inflammatory bowel disease (IBD) involves many factors, including environmental parameters, microorganisms, and the immune system. Although research on IBD continues to expand, the specific pathogenesis mechanism is still unclear. Protein modification refers to chemical modification after protein biosynthesis, also known as post-translational modification (PTM), which causes changes in the properties and functions of proteins. Since proteins can be modified in different ways, such as acetylation, methylation, and phosphorylation, the functions of proteins in different modified states will also be different. Transitions between different states of protein or changes in modification sites can regulate protein properties and functions. Such modifications like neddylation, sumoylation, glycosylation, and acetylation can activate or inhibit various signaling pathways (e.g., nuclear factor-‍κB (NF-‍κB), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT)) by changing the intestinal flora, regulating immune cells, modulating the release of cytokines such as interleukin-1β (IL-‍‍1β), tumor necrosis factor-α (TNF‍-‍α), and interferon-‍γ (IFN-‍γ), and ultimately leading to the maintenance of the stability of the intestinal epithelial barrier. In this review, we focus on the current understanding of PTM and describe its regulatory role in the pathogenesis of IBD.

The Regulatory Network on Acetylation of the Tumor Suppressor p53 / 中国生物化学与分子生物学报

p53 represents one of the most important tumor suppressors in mammalian cells, and the posttranslational modifications (PTMs) serve as a major strategy for fine-tuning of the functions of p53 in cells. Particularly, the acetylation regulates either the overall transactivity of p53 or the p53-dependent transcriptional selectivity, which plays key roles in modulating a variety of biological processes including cell cycle arrest, apoptosis, senescence, autophagy, and metabolism. This review, starting with the timeline of the researches on p53 acetylation, firstly summarizes how the site-specific acetylation of p53 is built up, including the acetyltransferases that catalyze p53 acetylation and their regulatory mechanism that influencing p53 functions. Secondly, this review summarizes pivotal deacetylases that erase p53 acetylation, and their contributions in modulating p53 cellular activities. Additionally, this review summarizes the reader proteins that specifically recognize and bind to acetylated/ unacetylated residues of p53, and their intimate interactions with p53 in manipulating downstream targets transcriptions. Meanwhile, this review sums up the crosstalk mechanisms between the acetylation and other PTMs in regulating p53 biological functions. Lastly, this review proposes a perspective on the studies of p53 acetylation in the field of molecular biomedicine in future.

Lysine Acetyltransferase 5 and Tumor / 中国生物化学与分子生物学报

Lysine acetyltransferase 5 (KAT5), a member of the MYST family, can participate in cellular processes such as transcription, DNA repair, differentiation and signal transduction by acetylating different substrates. The role of KAT5 cannot be replaced by other MYST family members, and the knockout of KAT5 can directly lead to apoptosis, indicating that KAT5 may be located in the upstream of physiological signaling pathways in cells and play an extremely important and unique role. Therefore, the changes in KAT5 expression are very likely to lead to the occurrence and development of tumors. Previous studies have found that KAT5 is downregulated in breast cancer, melanoma, and lung cancer, and is considered a tumor suppressor in these tumors. However, in recent years, studies have found that KAT5 can be either highly or lowly expressed in breast cancer, liver cancer, melanoma, prostate cancer, lung cancer and other tumors. On the premise of high KAT5 expression, KAT5 can play a tumor-promoting role. While on the premise of low KAT5 expression, KAT5 can also play as a tumor suppressor. With further decrease of KAT5 expression, its tumor suppressive effect is weakened, which may lead to the occurrence and development of tumors. In addition, KAT5 has also been found to be differentially expressed in osteosarcoma, thyroid cancer, glioblastoma, colorectal cancer and other tumors, and the differential expression of KAT5 is closely related to the proliferation, metastasis, apoptosis, drug and radiotherapy resistance of tumor cells. Therefore, KAT5 is one of the potential tumor therapeutic targets. Here, we summarize the expression of KAT5 in tumors and the tumor-suppressing or tumor-promoting signaling pathways involved in the corresponding expression in recent years, hoping to provide new inspiration and reference for tumor treatment and prognosis monitoring.

Research progress of protein post-translational modification in hepatocellular carcinoma / 中国药理学通报

Liver cancer has the characteristics of high incidence rate, high malignancy and hidden disease.At present, the treat¬ment of liver cancer mainly includes surgery, radiotherapy and chemotherapy, but the prognosis is poor.Therefore, it is very important to explore the pathogenesis of liver cancer and find ef¬fective drugs on this basis.Protein post-translational modifica¬tion is a hot topic in epigenetics.Recent studies have found that the occurrence and development of liver cancer is related to the abnormality of post-translational modification, and can be used as a target for the diagnosis and treatment of liver cancer.This article reviews the relationship between the major protein post- translational modifications discovered in recent years and liver cancer, and provides clues for the diagnosis, treatment and prognosis of liver cancer.