Specific protein 1 (Sp1) is pivotal in sustaining baseline transcription as well as modulating cell signaling pathways and transcription factors activity. Through interactions with various proteins, especially transcription factors, Sp1 controls the expression of target genes, influencing numerous biological processes. Numerous studies have confirmed Sp1\'s significant regulatory role in the pathogenesis of cardiovascular disorders. Post-translational modifications (PTMs) of Sp1, such as phosphorylation, ubiquitination, acetylation, glycosylation, SUMOylation, and S-sulfhydration, can enhance or modify its transcriptional activity and DNA-binding stability. These modifications also regulate Sp1 expression across different cell types. Sp1 is crucial in regulating non-coding gene expression and the activity of proteins in response to pathophysiological stimuli. Understanding Sp1 PTMs advances our knowledge of cell signaling pathways in controlling Sp1 stability during cardiovascular disease onset and progression. It also aids in identifying novel pharmaceutical targets and biomarkers essential for preventing and managing cardiovascular diseases.

Specific protein 1 (Sp1) is central to regulating transcription factor activity and cell signaling pathways. Sp1 is highly associated with the poor prognosis of various cancers; it is considered a non-oncogene addiction gene. The function of Sp1 is complex and contributes to regulating extensive transcriptional activity, apart from maintaining basal transcription. Sp1 activity and stability are affected by post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, glycosylation, and SUMOylation. These modifications help to determine genetic programs that alter the Sp1 structure in different cells and increase or decrease its transcriptional activity and DNA binding stability in response to pathophysiological stimuli. Investigating the PTMs of Sp1 will contribute to a deeper understanding of the mechanism underlying the cell signaling pathway regulating Sp1 stability and the regulatory mechanism by which Sp1 affects cancer progression. Furthermore, it will facilitate the development of new drug targets and biomarkers, thereby elucidating considerable implications in the prevention and treatment of cancer.

BACKGROUND: Patients with lung adenocarcinoma (LUAD) generally have poor prognosis. The role of striatin-interacting protein 2 (STRIP2) in LUAD remain unclear.
METHODS: Liquid chromatography-mass spectrometry analyses were used to screen the STRIP2-binding proteins and co-immunoprecipitation verified these interactions. A dual luciferase reporter assay explored the transcription factor activating STRIP2 transcription. Xenograft and lung metastasis models assessed STRIP2\'s role in tumor growth and metastasis in vivo.
RESULTS: STRIP2 is highly expressed in LUAD tissues and is linked to poor prognosis. STRIP2 expression in LUAD cells significantly promoted cell proliferation, invasion, and migration in vitro and in vivo. Mechanistically, STRIP2 boosted the PI3K/AKT/mTOR/MYC cascades by binding AKT. In addition, specificity protein 1, potently activated STRIP2 transcription by binding to the STRIP2 promoter. Blocking STRIP2 reduces tumor growth and lung metastasis in xenograft models.
CONCLUSIONS: Our study identifies STRIP2 is a key driver of LUAD progression and a potential therapeutic target.

Oxyresveratrol (OxyR) exerts biological and pharmacological effects in a variety of tumor cells, including antioxidant action, antitumor activity, and proapoptotic effects. However, the regulation of targeted signaling pathways by OxyR and the mechanism underlying these effects in human renal cell carcinoma (RCC) have been less studied. We observed that OxyR at noncytotoxic doses did not affect the growth of human RCC cells or normal kidney HK2 cells. OxyR inhibited ACHN and Caki-1 cell migration and invasion through targeting matrix metalloproteinase 1 (MMP1) expression. Analysis of clinical databases showed that high MMP1 expression is associated with lower overall survival (OS) in these cancers (p < 0.01). OxyR significantly inhibited the mRNA and protein expression of Sp1. Furthermore, luciferase assay results showed that OxyR inhibited Sp1 transcriptional activity. Additionally, OxyR preferentially suppressed the activation of ERK and PKCα. Treatment with U0126 (MEK inhibitor) or G06976 (PKCα inhibitor) clearly decreased Sp1 and MMP1 expression and inhibited RCC cell migration and invasion. In conclusion, OxyR may be a potential antitumor therapy for the inhibition of migration and invasion by controlling p-ERK/Sp1 and p-PKCα/Sp1-mediated MMP1 expression in RCC.

Gliomas are the most prevalent malignancies of the central nervous system (CNS). Downregulation of microRNA‑124 (miR‑124) has been identified in glioma; however, its biological functions in glioma are not yet fully understood. Specificity protein 1 (SP1) is a type of transcription factor that is involved in cancer progression. In this study, we examined the targeting of Sp1 mRNA by miR-124-3p in a rat glioma model. After confirming and selecting the binding of Sp1 to miR-124 with the help of bioinformatics methods, adult male Wistar rats were used to induce glioma by microinjection of 1 × 106 C6 cells into the striatum area of brain. The rats were divided into 3 groups; intact, sham and glioma groups. The presence of glioma was confirmed 21 days after implantation through histological analysis. The expression levels of miR-124 and SP1 genes in the experimental groups were examined using quantitative real-time polymerase chain reaction (qRT-PCR). Our data showed that the expression of miR-124 was significantly downregulated in glioma group compared to the sham and intact group, while the expression of SP1 was significantly upregulated. We found that the expression levels of miR-124 and Sp1 were decreased and increased in C6 cell line compared to the normal brain tissue cell line, respectively. The results indicated that Sp1 was identified as a direct target of miR‑124 through luciferase reporter assays. In summary, this study demonstrated for the first time that miR-124 expression is downregulated and Sp1 expression is upregulated in an animal model of glioma, which, in turn, may be involved in the development of glioma brain cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

The mild hypothermia response (MHR) maintains organismal homeostasis during cold exposure and is thought to be critical for the neuroprotection documented with therapeutic hypothermia. To date, little is known about the transcriptional regulation of the MHR. We utilize a forward CRISPR-Cas9 mutagenesis screen to identify the histone lysine methyltransferase SMYD5 as a regulator of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia. This repression correlates with temperature-dependent levels of histone H3 lysine 26 trimethylation (H3K36me3) at the SP1 locus and globally, indicating that the mammalian MHR is regulated at the level of histone modifications. We have identified 37 additional SMYD5-regulated temperature-dependent genes, suggesting a broader MHR-related role for SMYD5. Our study provides an example of how histone modifications integrate environmental cues into the genetic circuitry of mammalian cells and provides insights that may yield therapeutic avenues for neuroprotection after catastrophic events.

In mammals, specificity protein 1 (SP1) was the first Cys2-His2 zinc finger transcription factor to be isolated within the specificity protein and Krüppel-like factor (Sp/KLF) gene family. SP1 regulates gene expression by binding to Guanine-Cytosine (GC)-rich sequences on promoter regions of target genes, affecting various cellular processes. Additionally, the activity of SP1 is markedly influenced by posttranslational modifications, such as phosphorylation, acetylation, glycosylation, and proteolysis. SP1 is implicated in the regulation of apoptosis, cell hypertrophy, inflammation, oxidative stress, lipid metabolism, plaque stabilization, endothelial dysfunction, fibrosis, calcification, and other pathological processes. These processes impact the onset and progression of numerous cardiovascular disorders, including coronary heart disease, ischemia-reperfusion injury, cardiomyopathy, arrhythmia, and vascular disease. SP1 emerges as a potential target for the prevention and therapeutic intervention of cardiac ailments. In this review, we delve into the biological functions, pathophysiological mechanisms, and potential clinical implications of SP1 in cardiac pathology to offer valuable insights into the regulatory functions of SP1 in heart diseases and unveil novel avenues for the prevention and treatment of cardiovascular conditions.

Hepatocellular carcinoma (HCC) is characterized with high recurrence and mortality, and the clinical treatments for HCC are very limited. Hepatocellular carcinoma stem cells are the root of HCC progress, recurrence, and multidrug resistance. Ovatodiolide (OVA) is a bioactive diterpenoid served as an inflammatory and immunotherapeutic responses modulator. In this research, we found OVA inhibited HCC stemness through inhibiting MTDH gene transcription. Moreover, we firstly discovered transcription factor SP1 bound to the promoter region of MTDH to transcriptionally regulate MTDH level. Mechanically, we demonstrated OVA decreased SP1 protein stability to transcriptionally inhibit MTDH gene, and inhibited the nuclear translocation of p65, and then diminished IL-6 level to suppress JAK/STAT3 signaling pathway, eventually decreases CD133 level and the stemness of HCC. Furthermore, we demonstrated ACT004, OVA derivative with high metabolic stability towards cytochrome P450 enzymes, showed no genotoxicity and no accumulative or delayed toxicities after long-term administration in rats. And the in vivo efficacy experiments indicated ACT004 inhibited tumor growth of hepatocellular carcinoma. In conclusion, we revealed the mechanism of OVA in regulating HCC stemness, detected the toxicity of OVA derivative and evaluated the in vivo efficacy which lays a foundation for further discovery of anti-HCC stem cell agents and provide a new strategy for the application of OVA in clinical treatment.

Esophageal cancer (EC), a prevalent malignancy, has a high incidence and mortality. X-ray repair cross complementing 2 (XRCC2) functions on DNA damage and repair that works the progression of various cancers. Nevertheless, the role and mechanism of XRCC2 remain unknown in EC. The XRCC2 expression was examined by reverse transcription quantitative polymerase chain reaction and western blot. The function of XRCC2 in EC were investigated through cell counting kit-8, colony formation, transwell, flow cytometry, chromatin immunoprecipitation, luciferase, and western blot experiments. Besides, the role of XRCC2 in EC was assessed by western blot and immunohistochemistry experiments after nude mice were injected with EC109 cells and treated with nab-paclitaxel. The XRCC2 expression was upregulated in EC. Knockdown of XRCC2 diminished cell viability, and the number of colonies, migration cells and invasion cells of KYSE150 and EC109 cells. Silencing of XRCC2 diminished the cell viability of both two cells with a lower IC50, whereas boosted the apoptosis rate of both cells with the treatment of albumin-paclitaxel. All these outcomes were reverse with the upregulation of XRCC2 in both two cells. Mechanically, XRCC2 was transcriptionally regulated by specificity protein 1 (SP1), and silencing of SP1 inhibited the cell growth of EC. In vivo, transfection of shXRCC2 with or without albumin-paclitaxel treatment both decreased the tumor size and weight, as well as the expression of XRCC2 and Ki-67 in xenografted mice. XRCC2 transcriptionally regulated by SP2 promoted proliferation, migration, invasion, and chemoresistance of EC cells.