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

Intervertebral disk 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 remain unclear. This study aimed to investigate the role of T-box transcription factor T (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. First, 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.NEW & NOTEWORTHY This study investigates the role of Tbxt in IDD. The results demonstrate that knockdown of Tbxt exacerbates H2O2-induced senescence and apoptosis in NPCs and IDD, whereas upregulation of Tbxt significantly protects against IDD both in vivo and in vitro. Mechanistically, in the nucleus, Tbxt enhances the transcription of ATG7, leading to increased expression of ATG7 protein levels. This, in turn, promotes elevated autophagy levels, ultimately alleviating IDD.

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.

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.

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.

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.

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 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.

A p53/LINC00324 positive feedback loop suppresses tumor growth by counteracting SET-mediated transcriptional repression.

The p53 tumor suppressor exerts antitumor functions through its ability to regulate the transcription of its downstream targets. Long noncoding RNAs (lncRNAs) act as oncogenes or tumor suppressors implicated in tumorigenesis and tumor progression. Here, we identify the lncRNA LINC00324 (long intergenic noncoding RNA 00324) as a direct p53 transcriptional target. Knockdown of LINC00324 expression promotes tumor growth by reducing p53 transcriptional activity, whereas ectopic LINC00324 expression demonstrates a reverse effect. Notably, LINC00324 is present in the endogenous p53 complex in tumor cells and directly binds to the C-terminal domain of p53 in vitro. Mechanistically, LINC00324 enables p53 transactivation by competitively disrupting the p53-SET interaction, resulting in an increase of p300/CBP-mediated H3K18 and H3K27 acetylation on the p53 target promoters. Lower LINC00324 expression is associated with more aggressive disease status and predicts worse overall survival of patients with cancer. Our study identifies a p53/LINC00324 positive feedback loop that suppresses tumor growth by counteracting SET-mediated transcriptional repression.

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.

Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2.

Posttranslational modifications represent a key step in modulating programmed death-1 (PD-1) functions, but the underlying mechanisms remain incompletely defined. Here, we report crosstalk between deglycosylation and ubiquitination in regulating PD-1 stability. We show that the removal of N-linked glycosylation is a prerequisite for efficient PD-1 ubiquitination and degradation. Murine double minute 2 (MDM2) is identified as an E3 ligase of deglycosylated PD-1. In addition, the presence of MDM2 facilitates glycosylated PD-1 interaction with glycosidase NGLY1 and promotes subsequent NGLY1-catalyzed PD-1 deglycosylation. Functionally, we demonstrate that the absence of T cell-specific MDM2 accelerates tumor growth by primarily upregulating PD-1. By stimulating the p53-MDM2 axis, interferon-α (IFN-α) reduces PD-1 levels in T cells, which, in turn, exhibit a synergistic effect on tumor suppression by sensitizing anti-PD-1 immunotherapy. Our study reveals that MDM2 directs PD-1 degradation via a deglycosylation-ubiquitination coupled mechanism and sheds light on a promising strategy to boost cancer immunotherapy by targeting the T cell-specific MDM2-PD-1 regulatory axis.

Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy.

Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of Usp2 in mice has no obvious effect in normal tissues. Moreover, no obvious toxicity is observed upon the USP2 inhibitor treatment in vivo as Mdm2-mediated regulation of p53 remains intact. Our study reveals a promising strategy for p53-based therapy by circumventing the toxicity issue.

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.

Study of the efficacy of 3D-printed prosthetic reconstruction after pelvic tumour resection.

The purpose of this study is to explore the effect of using 3D printed pelvic prosthesis to reconstruct bone defect after pelvic tumor resection. From June 2018 to October 2021, a total of 10 patients with pelvic tumors underwent pelvic tumor resection and 3D printed customized hemipelvic prosthesis reconstruction in our hospital. Enneking pelvic surgery subdivision method was used to determine the degree of tumor invasion and the site of prosthesis reconstruction. 2 cases in Zone I, 2 cases in Zone II, 3 cases in Zone I + II, 2 cases in Zone II + III and 1 case in Zone I + II + III. Patients had preoperative VAS scores of 6.5 ± 1.3, postoperative VAS scores of 2.2 ± 0.9, preoperative MSTS-93 scores of 9.4 ± 5.3 and postoperative 19.4 ± 5.9(p < 0.05), all patients had improvement in pain after surgery; Postoperative complications included joint dislocation in 2 cases, myasthenia caused by Guillain-Barre syndrome in 1 case, delayed wound healing in 3 cases and wound infection in 2 cases. Postoperative wound-related complications and dislocations were associated with the extent of the tumor. Patients with tumor invasion of the iliopsoas and gluteus medius muscles had higher complication rates and worse postoperative MSTS scores (p < 0.05). The patients were followed up for 8 ∼ 28 months. During the follow-up period, 1 case recurred, 4 cases metastasized and 1 case died. All pelvic CTs reviewed 3-6 months after surgery showed good alignment between the 3D printed prosthesis and the bone contact, and tomography showed the growth of trabecular structures into the bone. Overall pain scores decreased and functional scores improved in patients after 3D printed prosthesis replacement for pelvic tumor resection. Long-term bone ingrowth could be seen on the prosthesis-bone contact surface with good stability.

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.

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-SET-PP2A 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.

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.

Neutrophil-lymphocyte ratio as a risk factor for osteoporotic vertebrae fractures and femoral neck fractures.

Fracture is associated with osteopenia after osteoporosis. Neutrophil-lymphocyte ratio (NLR) is common in inflammatory diseases. NLR can be used as an effective clinical tool to assess postmenopausal osteoporosis. The aim of this study is to further explore the relationship between elevated NLR and the severity of osteoporotic vertebrae fractures and femoral neck fracture based on magnetic resonance imaging (MRI). A total of 80 patients with osteoporotic vertebrae fractures, osteoporotic femoral neck fracture in Baoding Second Central Hospital from 2017 to 2020 were selected as the research objects. This study included a series of pretreatment factors, mainly including white blood cell count, red blood cell count, hemoglobin, and the general condition of the patients. Statistical methods included Pearson chi-square test, Spearman correlation test, logistic regression analysis and receiver operator characteristic (ROC) curve. According to Pearson chi-square test, Spearman correlation test, univariate/multivariate logistic regression analysis, the severity of osteoporotic vertebrae fractures, osteoporotic femoral neck fracture was significantly correlated with NLR (P < .001). NLR (odds ratio [OR] = 13.229, 95% CI: 4.167-41.998, P < .001) was a significant independent risk factor for osteoporotic vertebrae fractures, osteoporotic femoral neck fracture. receiver operator characteristic (ROC) curve was used to detect the specificity and sensitivity. The level of NLR has an important influence on the severity of osteoporotic vertebrae fractures and femoral neck fracture. The higher the level of NLR, the more serious the osteoporotic vertebrae fractures and femoral neck fracture.

Apatinib Functioned as Tumor Suppressor of Synovial Sarcoma through Regulating miR-34a-5p/HOXA13 Axis.

Objective: Synovial sarcoma is a rare malignant tumor. The role of apatinib in synovial sarcoma remains unclear. In this study, we aimed to determine the biological functions and the potential molecular mechanism of action of apatinib in synovial sarcoma. Methods: SW982 cells were stimulated with apatinib. The relative expression of the genes was determined by performing qPCR. Protein levels were evaluated by western blot and immunohistochemistry assays. Proliferation, apoptosis, migration, and invasion of SW982 cells were determined by the CCK-8 assay, clone formation assay, flow cytometry, wound healing, and the transwell assay, respectively. Additionally, SW982 cells were injected into mice to induce synovial sarcoma. Results: Apatinib decreased the proliferation, migration, and invasion but increased the apoptosis of SW982 cells. Apatinib repressed tumor growth in vivo and elevated miR-34a-5p in SW982 cells. The inhibition of miR-34a-5p repressed the reduction of proliferation, migration, and invasion and also the elevation of apoptosis in apatinib-treated SW982 cells. The luciferase activity decreased after cotransfection of the miR-34a-5p mimic and the wild-type HOXA13 vector. Additionally, an increase in miR-34a-5p repressed the levels of HOXA13 mRNA and protein. Moreover, HOXA13 reversed these patterns caused by the inhibition of miR-34a-5p in apatinib-treated SW982 cells. Conclusion: Apatinib elevated miR-34a-5p and reduced HOXA13, leading to a significant decrease in proliferation, migration, and invasion, along with an enhancement of apoptosis in SW982 cells. Apatinib suppressed tumorigenesis and tumor growth in SW982 cells in vivo.

SGSM2 inhibits thyroid cancer progression by activating RAP1 and enhancing competitive RAS inhibition.

Thyroid cancer (TC) is one of the most common malignancies involving the head and neck, and its incidences are increasing every year. Small G protein signaling modulators 2 (SGSM2) belongs to a newly identified protein group that contributes to numerous cancer progression. However, its role in TC remains unknown. The aim of this study was to explore the functions and underlying molecular mechanism of SGSM2 in the progression of thyroid tumorigenesis. Here, we demonstrated that SGSM2 expression was markedly decreased in TC, and that lower SGSM2 expression was potentially related to worse patient prognosis. Meanwhile, the SGSM2 levels were not directly correlated with BRAF or RAS mutations in TC. Based on our functional analysis, ectopic SGSM2 expression strongly prevented cell proliferation, migration, invasion, and tumorigenic activity in TC cells that harbored wild type RAS. Mechanistically, we demonstrated that SGSM2 interacted with Small G protein Ras-associated protein 1(RAP1) and augmented its activity. Activated RAP1 then competitively suppressed RAS activation and thereby downregulated output of MAPK/ERK and PI3K/Akt networks, which are primary contributors of TC. In summary, the present study reports a tumor suppressive role of SGSM2 in TC. Moreover, we revealed the underlying molecular mechanism, thus providing a potential therapeutic target for TCs that harbor wild type RAS.

Deciphering the PTM codes of the tumor suppressor p53.

The genome guardian p53 functions as a transcription factor that senses numerous cellular stresses and orchestrates the corresponding transcriptional events involved in determining various cellular outcomes, including cell cycle arrest, apoptosis, senescence, DNA repair, and metabolic regulation. In response to diverse stresses, p53 undergoes multiple posttranslational modifications (PTMs) that coordinate with intimate interdependencies to precisely modulate its diverse properties in given biological contexts. Notably, PTMs can recruit 'reader' proteins that exclusively recognize specific modifications and facilitate the functional readout of p53. Targeting PTM-reader interplay has been developing into a promising cancer therapeutic strategy. In this review, we summarize the advances in deciphering the 'PTM codes' of p53, focusing particularly on the mechanisms by which the specific reader proteins functionally decipher the information harbored within these PTMs of p53. We also highlight the potential applications of intervention with p53 PTM-reader interactions in cancer therapy and discuss perspectives on the 'PTMomic' study of p53 and other proteins.