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.

Background: Adaptation to ER stress has been indicated to play an important role in resistance to therapy in human melanoma. However, the relationship between adaptation to ER stress and cell metastasis in human melanoma remains unclear. Methods: The relationship of adaptation to ER stress and cell metastasis was investigated using transwell and mouse metastasis assays. The potential molecular mechanism of KLF4 in regulating the adaptation to ER stress and cell metastasis was investigated using RNA sequencing analysis, q-RT-PCR and western blot assays. The transcriptional regulation of nucleobindin 2 (NUCB2) by KLF4 was identified using bioinformatic analysis, luciferase assay, and chromatin immunoprecipitation (ChIP). The clinical significance of KLF4 and NUCB2 was based on human tissue microarray (TMA) analysis. Results: Here, we demonstrated that KLF4 was induced by ER stress in melanoma cells, and increased KLF4 inhibited cell apoptosis and promoted cell metastasis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of NUCB2, facilitating its transcription. Additionally, an increase in KLF4 promoted melanoma ER stress resistance, tumour growth and cell metastasis by regulating NCUB2 expression in vitro and in vivo. Elevated KLF4 was found in human melanoma tissues, which was associated with NUCB2 expression. Conclusion: Our data revealed that the promotion of ER stress resistance via the KLF4-NUCB2 axis is essential for melanoma cell metastasis, and KLF4 may be a promising specific target for melanoma therapy.

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) has been reported to play an oncogenic role in several cancers. However, the biological functions and regulatory mechanism of NUCKS1 in osteosarcoma have not been fully understood. In this study, we reported that NUCKS1 was significantly increased in osteosarcoma. Depletion of NUCKS1 decreased osteosarcoma cell proliferation and metastasis in vivo and in vitro. Overexpression of NUCKS1 accelerated osteosarcoma cell aggressiveness. Mechanistically, NUCKS1 facilitated asparagine (Asn) synthesis by transcriptionally upregulating asparagine synthetase (ASNS) expression and elevating the levels of Asn in osteosarcoma cells, leading to increased cell growth and metastasis. Inhibition of ASNS or reduction of Asn decreased osteosarcoma cell aggressiveness and impaired the promoting effects of NUCKS1 on tumorigenesis and metastasis. Furthermore, we also found that by acting as a sponge for miR-4768-3p, LINC00629 promoted NUCKS1 expression. Collectively, our findings highlight the role of NUCKS1 in regulating asparagine metabolism and reveal that LINC00629 is an important regulator of NUCKS1 that contributes to NUCKS1 upregulation in osteosarcoma.

Background: Escaping from ER stress-induced apoptosis plays an important role in the progression of many tumours. However, its molecular mechanism in osteosarcoma remains incompletely understood. Methods: The molecular mechanism was investigated using RNA sequencing, qRT–PCR and Western blot assays. The relationship between LINC00629 and KLF4 was investigated using RNA pulldown and ubiquitylation assays. The transcriptional regulation of laminin subunit alpha 4 (LAMA4) by KLF4 was identified using bioinformatic analysis, a luciferase assay, and a chromatin immunoprecipitation assay. Results: Here, we demonstrated that LINC00629 was increased under ER stress treatment. Elevated LINC00629 inhibited ER stress-induced osteosarcoma cell apoptosis and promoted clonogenicity and migration in vitro and in vivo. Further mechanistic studies indicated that LINC00629 interacted with KLF4 and suppressed its degradation, which led to a KLF4 increase in osteosarcoma. In addition, we also found that KLF4 upregulated LAMA4 expression by directly binding to its promoter and that LINC00629 inhibited ER stress-induced apoptosis and facilitated osteosarcoma cell clonogenicity and metastasis by activating the KLF4-LAMA4 pathway. Conclusion: Collectively, our data indicate that LINC00629 is a critical long noncoding RNA (lncRNA) induced by ER stress and plays an oncogenic role in osteosarcoma cell by activating the KLF4-LAMA4 axis.

Scutellarin, an active flavone extracted from Erigeron breviscapus, is known to exhibit antitumour activity in many cancers. However, the effects of Scutellarin on osteosarcoma remain unclear. In this study, we found that Scutellarin suppressed osteosarcoma cell growth, induced cell apoptosis and inhibited tumorigenesis. Mechanistically, our data revealed that EGR1 was significantly increased under Scutellarin treatment. Increased EGR1 enhanced tumour‐suppressive effects of Scutellarin on osteosarcoma cells via transcriptionally downregulating LINC00857 expression. Additionally, we found that LINC00857 acted as a competitive endogenous RNA of miR‐150‐5p and inhibited the activity of miR‐150‐5p, which resulted in c‐Myc increase. Scutellarin could suppress c‐Myc protein levels through decreasing LINC00857 expression in osteosarcoma. Thus, these findings demonstrate that EGR1/ LINC00857/miR‐150‐5p/c‐Myc axis plays a key role in promoting anticancer effects of Scutellarin and Scutellarin might have potential clinical implication in osteosarcoma clinical treatment.