Additionally, our results demonstrated that KLF5 overexpression restored the suppression of the malignant properties of LUAD cells by USP38 knockdown. SUMOylation of USP38 enhances the deubiquitination and stability of KLF5, thereby augmenting the malignant progression of LUAD.

P1/2, N=162, Recruiting, Sapience Therapeutics

ML323 also reduced lipid accumulation, hepatic triglycerides, free fatty acids, and macrophage infiltration in the livers of HFD-fed mice. Taken together, we suggest that USP1 plays an important role in adipogenesis by regulating C/EBPβ ubiquitination, and USP1-specific inhibitor ML323 is a potential treatment option and further study by ML323 is needed for clinical application for metabolic disorders.

Therapeutically, we showed that a cell-penetrating dominant negative ATF5 peptide, CP-d/n-ATF5, inhibits neuroblastoma metastasis to the bone marrow and liver by inducing anoikis sensitivity in circulating tumor cells. Our study identified ATF5 as a metastasis promoter and CP-d/n-ATF5 as a potential anti-metastatic therapeutic agent for neuroblastoma.

After surgery, patients will continue ST101 QW + standard chemoradiation with temozolomide. ndGBM treated with neoadjuvant ST101 monotherapy shows extensive treatment effects on the tumors that have never been treated with chemoradiation. Stability of enhancing lesions after ST101 monotherapy may not reflect the extent of treatment effect as revealed by treatment-related necrosis in the resected tissue. Analyses of the pharmacodynamics effects of ST101 on GBM cells and tumor microenvironment will be completed and presented.

Mechanistically, the hypothesis is advanced that ELF5 can promote lung cancer cell proliferation through inhibiting adenomatous polyposis coli 2 and increasing the expression of cyclin D1, which is a critical downstream target of the Wnt pathway. Taken together, these findings support the notion that ELF5 exerts an essential role in the proliferation of lung adenocarcinoma cells and may be a therapeutic target for the treatment of lung adenocarcinoma.

circ-LDLRAD3 was overexpressed in exosomes isolated from DDP-resistant GC cells. circ-LDLRAD3 knockdown reduced DDP resistance and blocked the malignant development of DDP-resistant GC by modulating the miR-588/SOX5 pathway.

Moreover, circ_0084811 regulated E2F transcription factor 5 (E2F5) expression via sponging microRNA-18a-5p (miR-18a-5p) and microRNA-18b-5p (miR-18b-5p). circ_0084811 modulated RB progression via the miR-18a-5p/miR-18b-5p/E2F5 axis.

Our findings suggest that this model can be a prognostic indicator for CHOL patients.

P1/2, N=162, Recruiting, Sapience Therapeutics | Trial primary completion date: Oct 2022 --> Oct 2023

CircZDBF2 up-regulated RNF145 expression by sponging miR-362-5p and miR-500b-5p and recruiting CEBPB, thereby promoting OSCC progression via NFκB signaling pathway. The findings recommend circZDBF2 as a probable therapeutic target for OSCC.

Validation of the risk model using the aforementioned eight signature genes demonstrated the models strong reliability and stable predictive performance. The results of the present study indicated that the eight-gene (Hes family BHLH transcription factor 5, KIT ligand, methyltransferase-like 3, proteasome 26S subunit non-ATPase 1, Ras-related protein Rab-10, treacle ribosome biogenesis factor 1, YTH N6-methyladenosine RNA binding protein 2 and Zinc Finger CCCH-Type Containing 13) signature constructed by the model may be reliable in predicting the prognosis of patients with HCC.

exoASO-C/EBPβ is a novel therapeutic candidate that selectively targets and attenuates a critical transcription factor in immunosuppressive myeloid cells, resulting in reprogramming of TAMs and potent anti-tumor activity across multiple TAM-rich mouse models as a monotherapy.

Moreover, during differentiation, KRAS inhibition reduced the levels of extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), p38, and phosphatidylinositol 3 kinase (PI3K) activation. These results show that KRAS has unique regulatory effects on cell proliferation, autophagy, adipogenic differentiation, and lipid accumulation.

Expression of Gdf5, Sox5, Sox6, melanoma inhibitory activity, noggin, odd-skipped related transcription factor 2, matrilin 4, and versican was positively correlated with Dcx expression. Our results demonstrate that Dcx expression defines a subpopulation of Gdf5 cells with chondrogenic potentials in E12.5 mouse embryonic limbs.

Dual luciferase reporter, real-time quantitative PCR (RT-qPCR), western blot and chromatin immunoprecipitation (ChIP) assays indicated that the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) directly bound to the UBQLN4 core promoter region and activated its transcription, upregulating β-catenin and c-Myc expression to promote CRC progression. Thus, our findings suggest that UBQLN4 is a key oncogene in CRC and may be a promising target for the diagnosis and treatment of patients with CRC.

This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.

This combination therapy not only inhibited the accumulation of MDSCs, but also promoted the infiltration of CD4 and CD8 T cells in the tumors. In summary, HT is a potential immunomodulatory drug for the treatment of pancreatic cancer.

In addition, SCFA improved the DAI, colonic histology, and the expression of serum inflammatory factors in LPS-treated mice and cells, noting that SCFA alleviated intestinal inflammation in vitro and in vivo. To sum up, SCFA inhibited DUSP6 by upregulating miR-145 through CEBPB repression and thus prevented the development of intestinal inflammation.

CircFOXM1 positively regulated E2F5 expression, while miR-577 negatively regulated E2F5 expression. In conclusion, our data confirmed that circFOXM1 could serve as a sponge of miR-577 to enhance the progression of GBM by targeting E2F5, which revealed that circFOXM1 might be a biomarker for GBM treatment.

P1/2, N=162, Recruiting, Sapience Therapeutics | Trial completion date: Jan 2023 --> Jan 2024

ETV5 has a carcinogenic effect in HGSOC and can be used as a clinically effective biomarker to determine the prognosis of HGSOC patients.

Consistent with previous observations, we found that ironomycin accumulates in the lysosomes of AML cells leading to a sequestration of iron in this organelle but inhibitors of canonical ferroptosis, including ferrostatin-1 and liproxstatin-1 failed to prevent the activity of ironomycin. Finally, primary AML samples from patients clinically resistant or refractory to venetoclax were sensitive to ironomycin in monotherapy and even more in combination with venetoclax. These results demonstrate that the novel mechanism of ironomycin action can be leveraged to resensitize AML cells to venetoclax and substitute for cytotoxic drugs as a more effective therapeutic combination in the salvage setting.

The overexpression of KLF5 in liver cancer tissues and blood is closely related to the HCC clinical stage and prognosis. Moreover, KLF5 analysis is helpful for HCC diagnosis and differential diagnosis.

Herein, we found ATF5 as a novel component of the HIF1 transcription complex. The findings of the present study may provide new insights into the development of a novel and more efficient therapeutic strategy against ESCA. Video abstract.

ATF5 362TT and CT genotypes were associated with decreased risk to develop AAP and better disease outcome demonstrating a low risk for events and superior survival.

Moreover, ETV5 changed drug-sensitivity to palbociclib and dinaciclib. Therefore, therapeutic regimens targeting ETV5 may be promising in improving the efficacy of target-CDK treatment in CRC.

Targeting CALM2 may be a molecular strategy for both primary HCC treatment and prevention of metastasis or recurrence.

Acetylation of ELF5 promoted its ubiquitination and degradation, but was also essential for its antiproliferative effect against breast cancer, as overexpression of wild-type ELF5 and sustained acetylation-mimicking ELF5 mutant could inhibit the expression of its target gene CCND1. Taken together, the results demonstrated a novel regulation of ELF5 as well as shedding light on its important role in modulation of breast cancer progression.

Furthermore, direct interaction between STAT3 and C/EBPβ was confirmed by immunoprecipitation and proximity ligation assays. Taken together, these results suggest that STAT3 stabilizes C/EBPβ, thereby promoting cancer-associated inflammation.

Besides, MALAT1 knockdown decreased DDP resistance, inhibited cell proliferation, migration, invasion, and promoted cell apoptosis by sponging miR-1271-5p to downregulate E2F5 expression in DDP-resistant OC cell. We demonstrated that MALAT1 mediated DDP-resistant OC development through miR-1271-5p/E2F5 axis, providing the theoretical basis for OC therapy.

Therefore, elevated SNHG12 expression was associated with poor survival and unfavorable clinical outcomes in various cancers, and therefore might be a potential prognostic biomarker in human cancers. Abbreviations Akt: protein kinase B; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; ceRNA: competitive endogenous RNA; CNKI: China National Knowledge Infrastructure; CI: confidence interval; CCNE1: cyclin E1; COAD: colon adenocarcinoma; DM: distant metastasis; DFS: disease-free survival; EMT: epithelial-mesenchymal transition; FISH: fluorescence in situ hybridization; FIGO: the International Federation of Gynecology and Obstetrics; GEPIA: Gene Expression Profiling Interactive Analysis; HR: hazard ratio; HIFα: hypoxia-inducible factor 1 α; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LIHC: hepatocellular carcinoma; LNM: lymph node metastasis; mTOR: mechanistic target of rapamycin kinase; MMP-9: matrix metalloproteinase 9; MCL1: myeloid cell leukemia 1; MLK3: mixed-lineage protein kinase 3; N/A: not available; NOS: Newcastle-Ottawa Scale; OR: odd ratio; OS: overall survival; PSA: prostate-specific antigen; PI3K: phosphoinositide 3-kinase; qRT-PCR: quantitative real-time polymerase chain reaction; READ: rectum adenocarcinoma; RFS: recurrence-free survival; SARC: sarcoma; SNHG12: small nucleolar RNA host gene 12; STAT3: signal transducer and activator of transcription 3; SOX4: SRY-box transcription factor 4; SOX5: SRY-box transcription factor 5; STAD: stomach adenocarcinoma; TCGA: The Cancer Genome Atlas; TNM: tumor node metastasis; WWP1: WW domain-containing E3 ubiquitin protein ligase 1; WHO grade: World Health Organization grade; ZEB2: zinc finger E-box-binding homeobox 2.

In addition, silencing of TP53 abrogated the effect of E2F5 silencing in MCF7 cells. Collectively, the present results indicated that E2F5 participated in the carcinogenesis of breast cancer carrying wild‑type TP53 through suppression of TP53, while E2F5 had a pro‑proliferative but not anti‑apoptotic effect on breast cancer with TP53 mutation.

The findings of the present study reveal that miR-32 acts as a tumor suppressor in colon cancer cells and may have therapeutic implications in colon cancer treatment.

P1/2, N=156, Ongoing, Sapience Therapeutics, Inc.

In EC biopsies, TPX2 mRNA expression levels were higher (P50% compared with <50%; P<0.01), and in intermediate‑high recurrence risk tumors compared with low‑risk tumors (P<0.05). Further validation studies in larger and independent EC cohorts will contribute to confirm the prognostic value of TPX2.