Tbxt alleviates senescence and apoptosis of nucleus pulposus cells through Atg7 mediated autophagy activation during intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a significant cause of low back pain, characterized by excessive senescence and apoptosis of nucleus pulposus cells (NPCs). However, the precise mechanisms behind this senescence and apoptosis remains unclear. This study aimed to investigate the role of Tbxt in IDD both in vitro and in vivo, using a hydrogen peroxide (H2O2)-induced NPCs senescence and apoptosis model, as well as a rat acupuncture IDD model. Firstly, the expression of p16 and cleaved-caspase 3 significantly increased in degenerated human NPCs, accompanied by a decrease in Tbxt expression. Knockdown of Tbxt exacerbated senescence and apoptosis in the H2O2-induced NPCs degeneration model. Conversely, upregulation of Tbxt alleviated these effects induced by H2O2. Mechanistically, bioinformatic analysis revealed that the direct downstream target genes of Tbxt were highly enriched in autophagy-related pathways and overexpression of Tbxt significantly activated autophagy in NPCs. Moreover, the administration of the autophagy inhibitor, 3-methyladenine, impeded the impact of Tbxt on the processes of senescence and apoptosis in NPCs. Further investigation revealed that Tbxt enhances autophagy by facilitating the transcription of ATG7 through its interaction with a specific motif within the promoter region. In conclusion, this study suggests that Tbxt mitigates H2O2-induced senescence and apoptosis of NPCs by activating ATG7-mediated autophagy.

USP7 interacts with and destabilizes oncoprotein SET.

Oncoprotein SE translocation (SET) is frequently overexpressed in different types of tumors and correlated with poor prognosis of cancer patients. Targeting SET has been considered a promising strategy for cancer intervention. However, the mechanisms by which SET is regulated under cellular conditions are largely unknown. Here, by performing a tandem affinity purification-mass spectrometry (TAP-MS), we identify that the ubiquitin-specific protease 7 (USP7) forms a stable protein complex with SET in cancer cells. Further analyses reveal that the acidic domain of SET directly binds USP7 while both catalytic domain and ubiquitin-like (UBL) domains of USP7 are required for SET binding. Knockdown of USP7 has no effect on the mRNA level of SET. However, we surprisingly find that USP7 depletion leads to a dramatic elevation of SET protein levels, suggesting that USP7 plays a key role in destabilizing oncoprotein SET, possibly through an indirect mechanism. To our knowledge, our data report the first deubiquitinase (DUB) that physically associates with oncoprotein SET and imply an unexpected regulatory effect of USP7 on SET stability.

Genome-wide CRISPR screening reveals ADCK3 as a key regulator in sensitizing endometrial carcinoma cells to MPA therapy.

BACKGROUND: The effectiveness of conservative treatment of endometrial carcinoma (EC) with oral progesterone therapy, such as medroxyprogesterone acetate (MPA), can be blunted due to primary or acquired resistance, but the underlying mechanisms remain incompletely defined. METHODS: Genome-wide CRISPR screening was performed to identify potential regulators in response to MPA in Ishikawa cells. Crystal violet staining, RT-qPCR, western blotting, ChIP-qPCR and luciferase assays were employed to elucidate the p53-AarF domain-containing kinase 3 (ADCK3) regulatory axis and its roles in sensitizing EC cells to MPA treatment. RESULTS: ADCK3 is identified as a previously unrecognized regulator in response to MPA in EC cells. Loss of ADCK3 in EC cells markedly alleviated MPA-induced cell death. Mechanistically, loss of ADCK3 primarily suppresses MPA-mediated ferroptosis by abrogating arachidonate 15-lipoxygenase (ALOX15) transcriptional activation. Moreover, we validated ADCK3 as a direct downstream target of the tumor suppressor p53 in EC cells. By stimulating the p53-ADCK3 axis, the small-molecule compound Nutlin3A synergized with MPA to efficiently inhibit EC cell growth. CONCLUSIONS: Our findings reveal ADCK3 as a key regulator of EC cells in response to MPA and shed light on a potential strategy for conservative EC treatment by activating the p53-ADCK3 axis to sensitize MPA-mediated cell death.

A comparative study between two methods of delivery of chemotherapeutic agent in patients with bone and soft tissue sarcoma of lower extremity.

BACKGROUND: We aimed to compare the effects of peripherally inserted central catheters (PICC) and implantable venous access devices (TIVADs) in terms of complications and shoulder function in patients with malignant bone and soft tissue tumors of the lower extremities. METHODS: We analyzed 65 cases of TIVADs (chest wall) and 65 cases of PICC at the orthopedic department of the Fourth Hospital of Hebei Medical University between June 2019 and December 2021, which were diagnosed with malignant bone tumors or soft tissue tumors of the lower extremities (tumors had to be relatively sensitive to chemotherapy), received regular chemotherapy, with ≥ 14 cycles (42 weeks). The two groups were compared in terms of catheter indwelling time, catheter-related complications, Constant-Murley shoulder function score, and displacement of the position of the catheter end on the catheterization side. RESULTS: Compared to the PICC group, at six months after catheterization, the TIVADs group reported better outcomes for catheter indwelling time, catheter-related complications, and Constant-Murley score for the catheterization-side shoulder joint (p < 0.05). The TIVADs group also reported less displacement of the catheter end position after 180° abduction of the catheterization-side shoulder joint (p < 0.05). CONCLUSIONS: Compared with PICC, TIVADs can prolong catheter indwelling time, reduce catheter-related complications, and maintain shoulder joint function, which makes it an ideal venous-access approach when providing chemotherapy to patients with malignant bone and soft tissue tumors of the lower extremities.

Unilateral Modified Posterior Lumbar Interbody Fusion Combined With Contralateral Lamina Fenestration Treating Severe Lumbarspinal Stenosis: A Retrospective Clinical Study.

Study design: Retrospective study. Objectives: The traditional PLIF is routinely utilized in severe lumbar spinal stenosis to relief the nerve compression. Nevertheless, the removal of posterior tension-band structure and the denervation and atrophy of the paraspinal muscle affect the clinical efficacy. Therefore, unilateral modified PLIF combined with contralateral fenestration was performed to overcome above-mentioned drawbacks. Methods: 32 modified PLIF and 33 traditional PLIF cases were retrospectively included. Operation time, length of stay (LOS) and blood loss were recorded. VAS of low back pain and leg pain, ODI and Sf-36 score including physical function and body pain were assessed. Fusion rate, lumbar lordosis (LL), intervertebral angle (IVA) and intervertebral height index (IHI) were evaluated radiologically. Results: Modified group possessed less blood loss, shorter operation time and less LOS. Compared with traditional group, the VAS of back pain was lower at 6 months postoperatively (P < .05) and the ODI score was lower at 3 months postoperatively (P < .05) in modified group. Modified group exhibited better physical function 3 months postoperatively and lower body pain 6 months postoperatively in Sf-36 score (P < .05). No statistic difference in LL, IVA, IHI and fusion rate were observed between both groups. Conclusions: Our modified PLIF combining with contralateral fenestration procedure exhibited particular advantages in comparison to traditional PLIF. The preservation of posterior tension-band structure facilitates to less low back pain, low complication rate and early functional recovery.

Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode.

Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins, the mechanisms of acetylation-mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 (also known as TP53) was an early example of non-histone protein acetylation and its precise role remains unclear. Lysine acetylation often creates binding sites for bromodomain-containing 'reader' proteins. Here we use a proteomic screen to identify the oncoprotein SET as a major cellular factor whose binding with p53 is dependent on CTD acetylation status. SET profoundly inhibits p53 transcriptional activity in unstressed cells, but SET-mediated repression is abolished by stress-induced acetylation of p53 CTD. Moreover, loss of the interaction with SET activates p53, resulting in tumour regression in mouse xenograft models. Notably, the acidic domain of SET acts as a 'reader' for the unacetylated CTD of p53 and this mechanism of acetylation-dependent regulation is widespread in nature. For example, acetylation of p53 also modulates its interactions with similar acidic domains found in other p53 regulators including VPRBP (also known as DCAF1), DAXX and PELP1 (refs. 7, 8, 9), and computational analysis of the proteome has identified numerous proteins with the potential to serve as acidic domain readers and lysine-rich ligands. Unlike bromodomain readers, which preferentially bind the acetylated forms of their cognate ligands, the acidic domain readers specifically recognize the unacetylated forms of their ligands. Finally, the acetylation-dependent regulation of p53 was further validated in vivo by using a knock-in mouse model expressing an acetylation-mimicking form of p53. These results reveal that acidic-domain-containing factors act as a class of acetylation-dependent regulators by targeting p53 and, potentially, other proteins.

The Anatomical and Biomechanical Superiority of Novel Posterior En Bloc Elevation Cervical Laminoplasty.

Objectives. In this study, we performed a novel type of posterior en bloc elevation cervical laminoplasty (PEEL) to keep the integrity of the posterior structure, aiming to reduce axial symptoms complicated by a conventional cervical laminoplasty procedure. Methods. Twelve human cervical cadaveric spines (C2-T1) were sequentially tested in the following order: intact condition, open-door laminoplasty (ODL) through bilateral intermuscular approach (mini-invasive ODL), PEEL, and laminectomy (LN). After bilateral transecting at the junction of lamina and lateral mass through the tubular retraction system, the PEEL procedure symmetrically elevated all the posterior structure which was further stabilized with bone grafts and titanium plates. Computed tomography (CT) scan and biomechanical testing were performed after each condition. Results. Both mini-invasive ODL and PEEL procedures were accomplished with 2 small incisions on each side. Two types of laminoplasties could enlarge the spinal canal significantly both in cross-sectional area and anteroposterior diameter comparing with intact condition. The PEEL procedure demonstrated a significantly higher enlargement rate on a canal area and a symmetrical expansion pattern. Compared with intact condition, mini-invasive ODL performed from C3-C7 demonstrated significantly decreased motion in all testing directions except the flexion range of motion (ROM); the PEEL procedure showed mild and insignificant decrease on ROM in all directions. Laminectomy resulted in a statistically significant increase in all directions except the lateral bending ROM. Conclusions. Posterior en bloc elevation cervical laminoplasty can enlarge the canal more effectively and preserve better ROM after operation than the ODL procedure. Although technically challenging, the PEEL procedure probably would decrease the common complications associated with ODL laminoplasty.

Transactivation of SOX5 by Brachyury promotes breast cancer bone metastasis.

The bone marrow has been long known to host a unique environment amenable to colonization by metastasizing tumor cells. Yet, the underlying molecular interactions which give rise to the high incidence of bone metastasis (BM) in breast cancer patients have long remained uncharacterized. In our study, in vitro and in vivo assays demonstrated that Brachyury (Bry) could promote breast cancer BM. Bry drives epithelial-mesenchymal transition (EMT) and promotes breast cancer aggressiveness. As an EMT driver, SOX5 involves in breast cancer metastasis and the specific function in BM. Chromatin immunoprecipitation (ChIP) assays revealed SOX5 is a direct downstream target gene of Bry. ChIP analysis and reporter assays identified two Bry-binding motifs; one consistent with the classic conserved binding sequence and the other a new motif sequence. This study demonstrates for the first time that Bry promotes breast cancer cells BM through activating SOX5. In clinical practice, targeting the Bry-Sox5-EMT pathway is evolving into a promising avenue for the prevention of bone metastatic relapse, therapeutic resistance and other aspects of breast cancer progression. Brachyury directly regulates the expression of SOX5 by binding to two motifs in its promoter region. The Bry-SOX5-EMT pathway may represent a potential target to develop treatments to prevent and treat bone metastasis from breast cancer.

Fibroblast growth factor-2 promotes the function of tendon-derived stem cells in Achilles tendon restoration in an Achilles tendon injury rat model.

The prognosis of Achilles tendon rupture is often unsatisfactory. Proliferative fibrous tissues and disordered collagen bundles make it difficult to guarantee normal biomechanical properties. The present study aimed to investigate the role of fibroblast growth factor-2 (FGF-2) in promoting the ability of human tendon-derived stem cells (hTDSCs) to treat Achilles tendon injury. hTDSCs were isolated from fetal Achilles tendon tissue and verified using fluorescence activated cell sorting analysis and multi-directional differentiation. The cells were then transfected with a lentivirus carrying the FGF2 gene. In vitro, FGF2 overexpression increased the expression of Collagen Type III Alpha 1 Chain (collagen-III) and scleraxis BHLH transcription factor (SCXA) significantly. Additionally, FGF-2-hTDSCs were transplanted into a rat Achilles tendon defect model. The in vivo results showed that the Achilles tendon tissue in the FGF-2 group secreted more extracellular matrix and produced collagen fibers that showed a more orderly arrangement. The expression of collagen-I and III in the FGF-2 group was significantly increased at 4 weeks postoperatively compared with the control group. Moreover, biomechanical tests showed that the failure load of FGF-2 group was higher at 4 and 8 weeks postoperatively than that of the controls. FGF-2 group had the highest stiffness in the early postoperative period, but showed no significant difference in the middle and late postoperative periods compared with that of the controls. In conclusion, FGF2 gene-modified hTDSCs promoted healing of Achilles tendon injury more effectively than hTDSCs alone.

SET7/9 regulates cancer cell proliferation by influencing ß-catenin stability.

ß-Catenin, which is a key mediator of the wingless-integration site (Wnt)/ß-catenin signaling pathway, plays an important role in cell proliferation, cell fate determination, and tumorigenesis, by regulating the expression of a wide range of target genes. Although a variety of posttranslational modifications are involved in ß-catenin activity, the role of lysine methylation in ß-catenin activity is largely unknown. In this study, su(var)3-9, enhancer-of-zeste, trithorax (SET) domain-containing protein 7 (SET7/9), a lysine methyltransferase, interacted with and methylated ß-catenin, as demonstrated both in vitro and in vivo. The interaction and methylation were significantly enhanced in response to H2O2 stimulation. A mutagenesis assay and mass spectrometric analyses revealed that ß-catenin was monomethylated by SET7/9 at lysine residue 180. Methylated ß-catenin was easily recognized by phosphokinase glycogen synthase kinase (GSK)-3ß for degradation. Consistent with this finding, the mutated ß-catenin (K180R) that cannot be methylated exhibited a longer half-life than did the methylated ß-catenin. The consequent depletion of SET7/9 by shRNA or the mutation of the ß-catenin (K180R) significantly enhanced the expression of Wnt/ß-catenin target genes such as c-myc and cyclin D1 and promoted the growth of cancer cells. Together, these results provide a novel mechanism by which Wnt/ß-catenin signaling is regulated in response to oxidative stress.

Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability.

Suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, catalyzes histone 3 lysine 9 trimethylation and is involved in heterochromatin organization and genome stability. However, the mechanism for regulation of the enzymatic activity of SUV39H1 in cancer cells is not yet well known. In this study, we identified SET domain-containing protein 7 (SET7/9), a protein methyltransferase, as a unique regulator of SUV39H1 activity. In response to treatment with adriamycin, a DNA damage inducer, SET7/9 interacted with SUV39H1 in vivo, and a GST pull-down assay confirmed that the chromodomain-containing region of SUV39H1 bound to SET7/9. Western blot using antibodies specific for antimethylated SUV39H1 and mass spectrometry demonstrated that SUV39H1 was specifically methylated at lysines 105 and 123 by SET7/9. Although the half-life and localization of methylated SUV39H1 were not noticeably changed, the methyltransferase activity of SUV39H1 was dramatically down-regulated when SUV39H1 was methylated by SET7/9. Consequently, H3K9 trimethylation in the heterochromatin decreased significantly, which, in turn, led to a significant increase in the expression of satellite 2 (Sat2) and α-satellite (α-Sat), indicators of heterochromatin relaxation. Furthermore, a micrococcal nuclease sensitivity assay and an immunofluorescence assay demonstrated that methylation of SUV39H1 facilitated genome instability and ultimately inhibited cell proliferation. Together, our data reveal a unique interplay between SET7/9 and SUV39H1--two histone methyltransferases--that results in heterochromatin relaxation and genome instability in response to DNA damage in cancer cells.

Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1).

Numerous studies indicate that Sirtuin 1 (SIRT1), a mammalian nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase (HDAC), plays a crucial role in p53-mediated stress responses by deacetylating p53. Nevertheless, the acetylation levels of p53 are dramatically increased upon DNA damage, and it is not well understood how the SIRT1-p53 interaction is regulated during the stress responses. Here, we identified Set7/9 as a unique regulator of SIRT1. SIRT1 interacts with Set7/9 both in vitro and in vivo. In response to DNA damage in human cells, the interaction between Set7/9 and SIRT1 is significantly enhanced and coincident with an increase in p53 acetylation levels. Importantly, the interaction of SIRT1 and p53 is strongly suppressed in the presence of Set7/9. Consequently, SIRT1-mediated deacetylation of p53 is abrogated by Set7/9, and p53-mediated transactivation is increased during the DNA damage response. Of note, whereas SIRT1 can be methylated at multiple sites within its N terminus by Set7/9, a methylation-defective mutant of SIRT1 still retains its ability to inhibit p53 activity. Taken together, our results reveal that Set7/9 is a critical regulator of the SIRT1-p53 interaction and suggest that Set7/9 can modulate p53 function indirectly in addition to acting through a methylation-dependent mechanism.

A method of percutaneous vertebroplasty under the guidance of two C-arm fluoroscopes.

OBJECTIVE: To compare the clinical application in the percutaneous vertebroplasty under the guidance of one or two C-arm fluoroscopes. METHODS: One hundred forty three elderly patients with Osteoporotic vertebral compression fractures (OVCFs) underwent percutaneous vertebroplasty under the guidance of one or two C-arm fluoroscopes. The number of pulsed imagings, the time of operation and the incidence of cement leakage were recorded. RESULTS: The average number of pulsed imagings was 16.00±1.58 vs 13.07±2.00 per patient under the guidance of one vs two C-arm fluoroscopes. The average time of operation was 48.42±5.00 minutes vs 39.70±7.42 minutes per patient under the guidance of one vs two C-arm fluoroscopes. The incidence of cement leakage was 20% vs 15.7% of the patients under the guidance of one vs two C-arm fluoroscopes. The differences in the number of pulsed imagings and the time of operation were statistically significant. The difference in incidence of cement leakage was not statistically significant. CONCLUSION: The two-fluoroscopic technique reduce the labor cost, the radiation, the time of operation and the operation risk.

Interplay between posttranslational modifications and liquid‒liquid phase separation in tumors.

Liquid‒liquid phase separation (LLPS) is a general phenomenon recently recognized to be critically involved in the regulation of a variety of cellular biological processes, such as transcriptional regulation, heterochromatin formation and signal transduction, through the compartmentalization of proteins or nucleic acids into droplet-like condensates. These processes are directly or indirectly related to tumor initiation and treatment. Posttranslational modifications (PTMs), which represent a rapid and reversible mechanism involved in the functional regulation of proteins, have emerged as key events in modulating LLPS under physiological or pathophysiological conditions, including tumorigenesis and antitumor therapy. In this review, we introduce the biological functions participated in cancer-associated LLPS, discuss the potential roles of LLPS during tumor onset or therapy, and emphasize the mechanistic characteristics of LLPS regulated by PTMs and its effects on tumor progression. We then provide a perspective on further studies on LLPS and its regulation by PTMs in cancer research. This review aims to broaden the understanding of the functions of LLPS and its regulation by PTMs under normal or aberrant cellular conditions.

Oncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis.

Metastasis is the major cause of lung cancer-related death, but the mechanisms governing lung tumor metastasis remain incompletely elucidated. SE translocation (SET) is overexpressed in lung tumors and correlates with unfavorable prognosis. Here we uncover SET-associated transcription factor, zinc finger and BTB domain-containing protein 11 (ZBTB11), as a prometastatic regulator in lung tumors. SET interacts and collaborates with ZBTB11 to promote lung cancer cell migration and invasion, primarily through SET-ZBTB11 complex-mediated transcriptional activation of matrix metalloproteinase-9 (MMP9). Additionally, by transcriptional repression of proline-rich Gla protein 2 (PRRG2), ZBTB11 links Yes-associated protein 1 (YAP1) activation to drive lung tumor metastasis independently of SET-ZBTB11 complex. Loss of ZBTB11 suppresses distal metastasis in a lung tumor mouse model. Overexpression of ZBTB11 is recapitulated in human metastatic lung tumors and correlates with diminished survival. Our study demonstrates ZBTB11 as a key metastatic regulator and reveals diverse mechanisms by which ZBTB11 modulates lung tumor metastasis.

Doxorubicin induces deglycosylation of cancer cell-intrinsic PD-1 by NGLY1.

Tumor cells can express the immune checkpoint protein programmed death-1 (PD-1), but how cancer cell-intrinsic PD-1 is regulated in response to cellular stresses remains largely unknown. Here, we uncover a unique mechanism by which the chemotherapy drug doxorubicin (Dox) regulates cancer cell-intrinsic PD-1. Dox upregulates PD-1 mRNA while reducing PD-1 protein levels in tumor cells. Although Dox shortens the PD-1 half-life, it fails to directly induce PD-1 degradation. Instead, we observe that Dox promotes the interaction between peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1) and PD-1, facilitating NGLY1-mediated PD-1 deglycosylation and destabilization. The maintenance of PD-1 sensitizes tumor cells to Dox-mediated antiproliferative effects. Our study unveils a regulatory mechanism of PD-1 in response to Dox and highlights a potential role of cancer cell-intrinsic PD-1 in Dox-mediated antitumor effects.

5-Aza-2'-deoxycytidine reactivates gene expression via degradation of pRb pocket proteins.

Not only does 5-aza-2'-deoxycytidine (5-aza-CdR) induce the reexpression of silenced genes through the demethylation of CpG islands, but it increases the expression of unmethylated genes. However, the mechanism by which 5-aza-CdR activates the expression of genes is not completely understood. Here, we report that the pRb pocket proteins pRb, p107, and p130 were degraded in various cancer cell lines in response to 5-aza-CdR treatment, and this effect was dependent on the proteasome pathway. Mouse double minute 2 (MDM2) played a critical role in this 5-aza-CdR-induced degradation of pRb. Furthermore, PP2A phosphatase-induced MDM2 dephosphorylation at S260 was found to be essential for MDM2 binding to pRb in the presence of 5-aza-CdR. pRb degradation resulted in the significant reexpression of several genes, including methylated CDKN2A, RASFF1A, and unmethylated CDKN2D. Finally, knockdown of pRb pocket proteins by either RNAi or 5-aza-CdR treatment induced a significant decrease in the recruitment of SUV39H1 and an increase in the enrichment of KDM3B and KDM4A to histones around the promoter of RASFF1A and thus reduced H3K9 di- and trimethylation, by which RASFF1A expression is activated. Our data reveal a novel mechanism by which 5-aza-CdR induces the expression of both methylated and unmethylated genes by degrading pRb pocket proteins.

[The biological functions of lysine methyltransferase PR-SET7].

PR-SET7 (also named SET8 or KMT5a) is a sole lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20me1) in higher eukaryotes. The abundance of PR-SET7 is dynamically mediated by the distinct E3 ubiquitin ligases in different cell cycle phases. PR-SET7 is closely related to the regulation of cell proliferation, and the H4K20me1 catalyzed by PR-SET7 has been implicated in regulating the diverse biological processes, including DNA replication, chromosome condensation and the activation of DNA replication checkpoints. Loss of PR-SET7 results in mas-sive DNA damage, cell cycle arrest and induction of apoptosis. In addition, PR-SET7 involves in regulating the transcrip-tion of several genes, such as ERa, Wnt and p53. PR-SET7 is also essential for individual development and participates in the formation of genomic imprinting. Moreover, PR-SET7 has been reported to promote tumorigenesis and metastasis, sug-gesting that PR-SET7 may be a potential target for cancer treatment. In this review, we focus on analyzing the structure of PR-SET7 and factors influencing histone modification on regulation of PR-SET7, and discuss the mechanisms by which PR-SET7 modulates cell-cycle progression, gene transcription, individual development and tumorigenesis.

The next decade of SET: from an oncoprotein to beyond.

This year marks the fourth decade of research into the protein SET, which was discovered in 1992. SET was initially identified as an oncoprotein, but later, it was shown to be a multifaceted protein involved in regulating numerous biological processes under both physiological and pathophysiological conditions. SET dysfunction is closely associated with diseases, such as cancer and Alzheimer's disease. With the increasing understanding of how SET works and how it is regulated in cells, targeting aberrant SET has emerged as a potential strategy for disease intervention. In this review, we present a comprehensive overview of the advancements in SET studies, encompassing its biological functions, regulatory networks, clinical implications, and pharmacological inhibitors. Furthermore, we provide insights into the future prospects of SET research, with a particular emphasis on its promising potential in the realm of immune modulation.

Alternatively mechanistic insights into acetylation in p53-mediated transcriptional regulation of cancer cell-intrinsic PD-1.

Since the recent discovery of cancer cell-intrinsic programmed cell death protein-1 (PD-1), the mechanisms that manipulate PD-1 functions in tumor development beyond its immune checkpoint roles have become attractive research topics in oncology. Our previous study validated that PD-1 exists in lung cancer cells and is directly transactivated by p53 in a DNA-binding domain (DBD) acetylation-dependent manner. Here, we report that the carboxyl-terminal domain (CTD) of p53 likewise participates in PD-1 transcriptional regulation in cancer cells under different regulatory mechanisms. By mutating the lysine residues within the CTD to mimic either acetylation-deficient or fully acetylated status, we proved that acetylated CTD dramatically impeded p53-mediated transactivation of PD-1. Furthermore, we identified bromodomain-containing protein 4 (BRD4) as a transcriptional coactivator of p53 that facilitates p53-mediated PD-1 transcription. Mechanistically, BRD4 specifically bound to the unacetylated CTD of p53, while CTD acetylation almost completely destroyed the BRD4-p53 interaction and thus led to compromised PD-1 expression. Collectively, this study unveils an alternative mechanism of p53 acetylation-directed PD-1 transcriptional regulation, which would broaden our current understanding of the molecular regulatory network of cancer cell-intrinsic PD-1.