Background: Glioblastoma is associated with poor prognosis and high mortality. Although the use of first-line temozolomide can reduce tumor growth, therapy-induced stress drives stem cells out of quiescence, leading to chemoresistance and glioblastoma recurrence. The specificity protein 1 (Sp1) transcription factor is known to protect glioblastoma cells against temozolomide; however, how tumor cells hijack this factor to gain resistance to therapy is not known. Methods: Sp1 acetylation in temozolomide-resistant cells and stemlike tumorspheres was analyzed by immunoprecipitation and immunoblotting experiments. Effects of the histone deacetylase (HDAC)/Sp1 axis on malignant growth were examined using cell proliferation–related assays and in vivo experiments. Furthermore, integrative analysis of gene expression with chromatin immunoprecipitation sequencing and the recurrent glioblastoma omics data were also used to further determine the target genes of the HDAC/Sp1 axis. Results: We identified Sp1 as a novel substrate of HDAC6, and observed that the HDAC1/2/6/Sp1 pathway promotes self-renewal of malignancy by upregulating B cell-specific Mo-MLV integration site 1 (BMI1) and human telomerase reverse transcriptase (hTERT), as well as by regulating G2/M progression and DNA repair via alteration of the transcription of various genes. Importantly, HDAC1/2/6/Sp1 activation is associated with poor clinical outcome in both glioblastoma and low-grade gliomas. However, treatment with azaindolyl sulfonamide, a potent HDAC6 inhibitor with partial efficacy against HDAC1/2, induced G2/M arrest and senescence in both temozolomide-resistant cells and stemlike tumorspheres. Conclusion: Our study uncovers a previously unknown regulatory mechanism in which the HDAC6/Sp1 axis induces cell division and maintains the stem cell population to fuel tumor growth and therapeutic resistance.

Our recent study indicated that overexpression of Sp1 enhances the proliferation of lung cancer cells, while represses metastasis. In this study, we found that the transcriptional activity of FOXO3 was increased, but its protein levels decreased following Sp1 expression. Sp1 increased expression of miR-182, which was then recruited to the 3’-untranslated region of FOXO3 mRNA to silence its translational activity. Knockdown of miR-182 inhibited lung cancer cells growth, but enhanced the invasive and migratory abilities of these cells through increased N-cadherin expression. Repression of FOXO3 expression in the miR-182 knockdown cells partially reversed this effect, suggesting that miR-182 promotes cancer cell growth and inhibits cancer metastatic activity by regulating the expression of FOXO3. The expression of several cancer metastasis-related genes such as ADAM9, CDH9 and CD44 was increased following miR-182 knockdown. In conclusion, in the early stages of lung cancer progression, Sp1 stimulates miR-182 expression, which in turn decreases FOXO3 expression. This stimulates proliferation and tumor growth. In the late stages, Sp1 and miR-182 decline, thus increasing FOXO3 expression, which leads to lung metastasis.

Chitinase-3-like-1 (CHI3L1) is an evolutionarily conserved protein involved in key biological processes, including tissue remodeling, angiogenesis, and neuroinflammation. It has emerged as a significant player in various neurodegenerative diseases and brain disorders. Elevated CHI3L1 levels have been observed in neurological conditions such as traumatic brain injury (TBI), Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), multiple sclerosis (MS), Neuromyelitis optica (NMO), HIV-associated dementia (HAD), Cerebral ischemic stroke (CIS), and brain tumors. This review explores the role of CHI3L1 in the pathogenesis of these disorders, with a focus on its contributions to neuroinflammation, immune cell infiltration, and neuronal degeneration. As a key regulator of neuroinflammation, CHI3L1 modulates microglia and astrocyte activity, driving the release of proinflammatory cytokines that exacerbate disease progression. In addition to its role in disease pathology, CHI3L1 has emerged as a promising biomarker for the diagnosis and monitoring of brain disorders. Elevated cerebrospinal fluid (CSF) levels of CHI3L1 have been linked to disease severity and cognitive decline, particularly in AD and MS, highlighting its potential for clinical diagnostics. Furthermore, therapeutic strategies targeting CHI3L1, such as small-molecule inhibitors and neutralizing antibodies, have shown promise in preclinical studies, demonstrating reduced neuroinflammation, amyloid plaque accumulation, and improved neuronal survival. Despite its therapeutic potential, challenges remain in developing selective and safe CHI3L1-targeted therapies, particularly in ensuring effective delivery across the blood–brain barrier and mitigating off-target effects. This review addresses the complexities of targeting CHI3L1, highlights its potential in precision medicine, and outlines future research directions aimed at unlocking its full therapeutic potential in treating neurodegenerative diseases and brain pathologies.

The exact mechanism underlying increases in Sp1 and the physiological consequences thereafter remains unknown. In rat primary cortical neurons, oxygen-glucose deprivation (OGD) causes an increase in H ₂ O ₂ as well as Sp1 in early ischaemia but apparently does not change mRNA level or Sp1 stability. We hereby identified a longer 5′-UTR in Sp1 mRNA that contains an internal ribosome entry site (IRES) that regulates rapid and efficient translation of existing mRNAs. By using polysomal fragmentation and bicistronic luciferase assays, we found that H ₂ O ₂ activates IRES-dependent translation. Thus, H ₂ O ₂ or tempol, a superoxide dismutase-mimetic, increases Sp1 levels in OGD-treated neurons. Further, early-expressed Sp1 binds to Sp1 promoter to cause a late rise in Sp1 in a feed-forward manner. Short hairpin RNA against Sp1 exacerbates OGD-induced apoptosis in primary neurons. While Sp1 levels increase in the cortex in a rat model of stroke, inhibition of Sp1 binding leads to enhanced apoptosis and cortical injury. These results demonstrate that neurons can use H ₂ O ₂ as a signalling molecule to quickly induce Sp1 translation through an IRES-dependent translation pathway that, in cooperation with a late rise in Sp1 via feed-forward transcriptional activation, protects neurons against ischaemic damage.