BET inhibitors enhance the anti-cancer effect of etoposide by suppressing the MRN-ATM axis in the DNA damage response

Etoposide is widely used for cancer chemotherapy in the clinic.However,long-term etoposide treatment can lead to adverse effects or drug resistance.To improve the situation,we evaluated the therapeutic efficiency of etoposide combined with inhibitors of bromodomain and extraterminal(BET)family proteins,which have recently emerged as novel anti-cancer targets due to their critical roles in cancer development.Firstly,we showed BRD4,one of the main targets of BET inhibitors,was involved in DNA damage response(DDR)via the homologous recombination(HR)repair pathway.

The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy

The oncoprotein SET is frequently overexpressed in many types of tumors and contributes to malignant initiation and progression through multiple mechanisms,including the hijacking of the tumor suppressors p53 and PP2A.Targeting aberrant SET represents a promising strategy for cancer intervention.However,the mechanism by which endogenous SET is regulated in cancer cells remains largely unknown.Here,we identified the tumor suppressor p53 as a key regulator that transcriptionally repressed the expression of SET in both normal and cancer cells.In addition,p53 stimulated PP2A phosphatase activity via p53-mediated transcriptional repression of SET,whereby SET-mediated inhibition of PP2A was alleviated.Moreover,targeting the interaction between SET and PP2A catalytic subunit(PP2Ac)with FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55(Thr55).Therefore,our findings uncovered a previously unknown p53-SETPP2A regulatory feedback loop.To functionally potentiate this feedback loop,we designed a combined therapeutic strategy by simultaneously administrating a p53 activator and SET antagonist in cancer cells and observed a dramatic synergistic effect on tumor suppression.Our study reveals mechanistic insight into the regulation of the oncoprotein SET and raises a potential strategy for cancer therapy by stimulating the p53-SET-PP2A feedback loop.

HDAC6 inhibitor loaded bimetallene nanosheets with antagonizing thermoresistance for augmented mild photothermal therapy

Photothermal therapy(PTT)induces thermoresistance through cellular heat shock response,which impairs the therapeutic efficacy of the PTT.To resolve this problem,we developed a photothermal theranostics(denoted as PMH),which integrated the photothermal conversion agent of PdMo bimetallene with histone deacetylase 6(HDAC6)selected inhibitor(ACY-1215),showing the synergistic antitumor effect both in vitro and in vivo.Mechanistically,under the photoacoustic imaging(PA)navigation,the released ACY-1215 triggered by NIR laser irradiation decrease the heat shock proteins(HSPs)expression and weaken the HDAC6-regulated HSP90 deacetylation,thus hindering the degradation of PTT-induced misfolded or unfold proteins through proteasome dependent pathway.Moreover,mild photothermal therapy(mPTT)treatment compromised the autophagy,which induced by HDAC6 inhibition,leading to mPTTinduced misfolded or unfold proteins further accumulation.Given that inhibition of HDAC6 plus m PTT contribute to tumor eradication.This study develops a promising combination strategy based on m PTT for future cancer treatment.

Applications of post-translational modifications of FoxO family proteins in biological functions

The functions of the FoxO family proteins,in particular their transcriptional activities,are modulated by post-translational modifi-cations(PTMs),including phosphorylation,acetylation,ubiquitination,methylation and glycosylation.These PTMs occur in response to different cellular stresses,which in turn regulate the subcellular localization of FoxO family proteins,as well as their half-life,DNA binding,transcriptional activity and ability to interact with other cellular proteins.In this review,we summarize the role of PTMs of FoxO family proteins in linking their biological and functional relevance with various diseases.

Histone modifications in DNA damage response

DNA damage is a relatively common event in eukaryotic cell and may lead to genetic mutation and even cancer. DNA damage induces cellular responses that enable the cell either to repair the damaged DNA or cope with the damage in an appropriate way. Histone proteins are also the fundamental building blocks of eukaryotic chromatin besides DNA, and many types of post-translational modifications often occur on tails of histones. Although the function of these modifications has remained elusive, there is ever-growing studies suggest that histone modifications play vital roles in several chromatin-based processes, such as DNA damage response. In this review, we will discuss the main histone modifications, and their functions in DNA damage response.

Bifurcation and chaos of a 4-side fixed rectangular thin plate in electromagnetic and mechanical fields

We studied the problem of bifurcation and chaos in a 4-side fixed rectangular thin plate in electromagnetic and me-chanical fields.Based on the basic nonlinear electro-magneto-elastic motion equations for a rectangular thin plate and the ex-pressions of electromagnetic forces,the vibration equations are derived for the mechanical loading in a steady transverse magnetic field.Using the Melnikov function method,the criteria are obtained for chaos motion to exist as demonstrated by the Smale horseshoe mapping.The vibration equations are solved numerically by a fourth-order Runge-Kutta method.Its bifurcation dia-gram,Lyapunov exponent diagram,displacement wave diagram,phase diagram and Poincare section diagram are obtained.

G9a/GLP catalyzes H3K14me1 and H3K14me2 in vivo and in vitro

Dear Editor,Chromatin modifications regulate multiple cellular progressions(Bannister and Kouzarides,2011;Zhang et al.,2021).Numerous histone modifications and their correspondent enzymes have been identified in the past decades(Huang et al.,2014)and more histone modification sites and types have been gradually identified in recent years(Kim et al.,2019;Lu et al.,2019).

Regulation of p53 acetylation

As a'genomic guardian',the tumor suppressor p53 plays key roles in maintaining homeostasis under physiological conditions and defending against tumorigenesis upon cellular exposure to internal or external stresses.Appropriate regulation of p53 is essential to ensure appropriate p53function,and this process is highly dependent on dynamic posttranslational modification(PTM,including acetylation,phosphorylation,ubiquitination et al.)of p53

A specific assay for JmjC domain-containing lysine demethylase and its application to inhibitor screening

Dear Editor, Chromatin is the macromolecular complex of DNA and histone proteins, which provides the scaffold for the packaging of our entire genome. In the basic unit of chromatin, the nucleosomes contain 147 base pairs of DNA, which is wrapped around a histone octamer, with two each of histones H2A, H2B, H3, and H4. Several types of post-translational modifications, including acetylation, phosphorylation, ubiquitination, and methylation, are possible on the tails of histones (Zhang et al., 2015). Combinations of these modifications determine the chromatin structure and transcriptional regulation of genes. Histone methylation is highlighted because of the specific dynamics related to gene regulation. Aberrant histone methylation has been observed in many types of tumors (Albert and Helin, 2010) and may contribute to the neoplastic transformation of cells (Chi et al., 2010). Histone lysine methylation is regulated by two classes of enzymes that have opposing activities: histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). To date, a number of mammalian KDMs have been discovered (Kooistra and Helin, 2012), and they have been separated into two classes: flavin adenine dinucleotide dependent oxidases, which were first discovered in 2004 (Shi et al., 2004), and Jumonji-C (JmjC) domain-containing enzymes, first identified in 2006 (Tsukada et al., 2006).

Intervening pyruvate carboxylase stunts tumor growth by strengthening anti-tumor actions of tumor-associated macrophages

Dear Editor,Tumor-associated macrophages(TAMs)are critical pro-tumor immunocytes and depletion of TAMs has been exploited for cancer therapy.1 However,the phenotypes and functions of TAMs are plastic,TAMs can also be effector cells by engulfing tumor cells and recruiting cytotoxic T cells,thus shaping the actions of TAMs is more scientific rational than depleting them indiscriminately.2 To promote the entry of reorienting TAMs into the clinical treatments of tumors,it is essential to explore the underline mechanisms controlling the anti-and pro-tumor activities of TAMs.