The deubiquitylase OTUD3 plays a suppressive role in breast tumorigenesis through stabilizing PTEN protein, but its role in lung cancer remains unclear. Here, we demonstrate that in vivo deletion of OTUD3 indeed promotes breast cancer development in mice, but by contrast, it slows down Kras^G12D-driven lung adenocarcinoma (ADC) initiation and progression and markedly increases survival in mice. Moreover, OTUD3 is highly expressed in human lung cancer tissues and its higher expression correlates with poorer survival of patients. Further mechanistic studies reveal that OTUD3 interacts with, deubiquitylates and stabilizes the glucose-regulated protein GRP78. Knockdown of OTUD3 results in a decrease in the level of GRP78 protein, suppression of cell growth and migration, and tumorigenesis in lung cancer. Collectively, our results reveal a previously unappreciated pro-oncogenic role of OTUD3 in lung cancer and indicate that deubiquitylases could elicit tumor-suppressing or tumor-promoting activities in a cell- and tissue-dependent context.

Background: The dismal prognosis of patients with glioma is largely attributed to cancer stem cells that display pivotal roles in tumour initiation, progression, metastasis, resistance to therapy, and relapse. Therefore, understanding how these populations of cells maintain their stem-like properties is critical in developing effective glioma therapeutics. Methods: RNA sequencing analysis was used to identify genes potentially involved in regulating glioma stem cells (GSCs). Integrin β4 (ITGB4) expression was validated by quantitative real-time PCR (qRT-PCR) and immunohistochemical (IHC) staining. The role of ITGB4 was investigated by flow cytometry, mammosphere formation, transwell, colony formation, and in vivo tumorigenesis assays. The reciprocal regulation between Integrin β4 and KLF4 was investigated by chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, immunoprecipitation, and in vivo ubiquitylation assays. Results: In this study, we found that ITGB4 expression was increased in GSCs and human glioma tissues. Upregulation of ITGB4 was correlated with glioma grades. Inhibition of ITGB4 in glioma cells decreased the self-renewal abilities of GSCs and suppressed the malignant behaviours of glioma cells in vitro and in vivo. Further mechanistic studies revealed that KLF4, an important transcription factor, directly binds to the promoter of ITGB4, facilitating its transcription and contributing to increased ITGB4 expression in glioma. Interestingly, this increased expression enabled ITGB4 to bind KLF4, thus attenuating its interaction with its E3 ligase, the von Hippel-Lindau (VHL) protein, which subsequently decreases KLF4 ubiquitination and leads to its accumulation. Conclusions: Collectively, our data indicate the existence of a positive feedback loop between KLF4 and ITGB4 that promotes GSC self-renewal and gliomagenesis, suggesting that ITGB4 may be a valuable therapeutic target for glioma.

Background: Chemotherapeutic insensitivity remains a big challenge in prostate cancer treatment. Recently, increasing evidence has indicated that KLF4 plays a key role in prostate cancer. However, the potential biological role of KLF4 in Chemotherapeutic insensitivity of prostate cancer is still unknown. Methods: The role of KLF4 in cisplatin-induced apoptosis was detected by western blotting and a cell counting kit (CCK8). The potential molecular mechanism of KLF4 in regulating prostate cancer chemosensitivity was investigated by RNA sequencing analysis, q-RT-PCR, western blotting and chromatin immunoprecipitation (ChIP). The expression level of KLF4 mediated by miR-32-5p was confirmed by bioinformatic analysis and luciferase assays. Results: Here, we found that KLF4 was induced by cisplatin in prostate cancer cells and that the increase in KLF4 promoted cell apoptosis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of BIK, facilitating its transcription. Additionally, we also found that the gene encoding KLF4 was a direct target of miR-32-5p. The downregulation of miR-32-5p in response to cisplatin treatment promoted KLF4 expression, which resulted in a increase in the chemosensitivity of prostate cancer. Conclusion: Thus, our data revealed that KLF4 is an essential regulator in cisplatin-induced apoptosis, and the miR-32-5p-KLF4-BIK signalling axis plays an important role in prostate cancer chemosensitivity.

Chemoresistance remains a major drawback to osteosarcoma treatment. ZBTB7A, a member of the POK transcription repressor family, was shown to play an important role in tumorigenesis. However, the effect of ZBTB7A on osteosarcoma chemoresistance is completely unknown. In this study, we found that ZBTB7A is increased in cisplatin-resistant osteosarcoma cells and that elevated ZBTB7A inhibits cisplatin-induced apoptosis by repressing LINC00473 expression. Further mechanistic studies revealed that ZBTB7A directly binds to the promoter and suppresses the transcription of LINC00473. Additionally, our data indicate that LINC00473 interacts with the transcript factor C/EBPβ, facilitating its binding to the promoter of IL24, leading to decrease chemoresistance. Thus, these findings indicate that the ZBTB7A-mediated LINC00473-C/EBPβ-IL24 pathway is a promising novel target for overcoming cisplatin resistance in osteosarcoma.