MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Abstract

JNK activity has been implicated in the malignant proliferation, invasion and drug‐resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c‐Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel‐like factor‐5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated‐SP1 and acetylated‐KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant‐negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c‐Jun activities was involved in the tumor‐growth inhibitory effects induced by LMK235 in U87‐xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c‐Jun signaling‐mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c‐Jun signaling in GCs.

MicroRNA-152 suppresses cell proliferation and tumor growth of bladder cancer by targeting KLF5 and MKK7

“…The luciferase reporter assay confirmed the target relationship between miR-152 and KLF5, as well as MKK7. Interestingly, the transcriptional factor KLF5 has been demonstrated to positively regulate MKK7 expression by binding with MKK7 promoter regions [11]. Our findings also indicate that MKK7 transcription was promoted by KLF5.…”

“…These data suggested that miR-152 suppressed KLF5 and MKK7 expressions via targeting the 3'UTR of their mRNAs. In addition, a previous study has revealed that the tran-scriptional factor KLF5 could positively regulate MKK7 expression by binding with MKK7 promoter regions [11]. In our study, the overexpression of KLF5 in 5637 and T24 cells significantly induced the mRNA expression of MKK7 ( p < 0.01, Figure 3F ).…”

“…A western blot was performed as previously described [11]. The primary antibodies used in this study included anti-DNMT1 (#5032S, 1:1,000, Cell Signaling Technology, Danvers, MA, USA), anti-KLF5 (#51586S, 1:1,000, Cell Signaling Technology, Danvers, MA, USA), anti-MKK7 (#4172S, 1:1,000, Cell Signaling Technology, Danvers, MA, USA), and anti-β-actin (ab8226, 1:500, Abcam, Cambridge, UK).…”

“…As an important component of the JNK cascade, mitogen-activated protein kinase kinase 7 (MKK7) has been reported to act as an oncogene in several types of cancers, such as lung cancer [9] and colorectal cancer [10]. Notably, a previous study has revealed that the transcriptional factor KLF5 could positively regulate MKK7 expression by binding with MKK7 promoter regions [11]. However, whether KLF5 interacts with MKK7 in regulating bladder cancer tumorigenesis remains unknown.…”

MiR-4310 induced by SP1 targets PTEN to promote glioma progression

“…The encoded protein is involved in many cellular processes, including cell differentiation, cell growth, apoptosis, immune responses, response to DNA damage, and chromatin remodeling. According to reports, SP1 plays important role in the tumorigenesis, progression, and drug resistance of gliomas [22][23][24][25]. We found that the promoter region of miR-4310 also contains GC-rich fragments.…”