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Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Further microarray studies in CYP2D6-humanized transgenic mice have shown that seven transcription factors, namely, activating transcription factor 5 (ATF5), early growth response 1 (EGR1), forkhead box protein A3 (FOXA3), JUNB, KLF9, KLF10, and REV-ERBα, are upregulated in mouse liver during pregnancy (Koh et al. 2014b). KLF9 itself is a weak transactivator of CYP2D6 promoter but significantly enhances CYP2D6 promoter transactivation by HNF-4α, a known transcriptional activator of CYP2D6 expression. The results from deletion and mutation analysis of CYP2D6 promoter activity have identified a KLF9 putative binding motif at the –22/-14 region to be critical in the potentiation of HNF-4α–induced transactivation of CYP2D6 (Koh et al. 2014b). KLF9, a member of the KLF transcription factor family of zinc finger DNA-binding proteins, can either activate or repress target gene expression in a promoter-specific context. KLF9 is involved in cell differentiation of B cells, keratinocytes, and neurons. Biologic actions of KLF9 are mediated either by its direct binding to the promoters of its target genes such as CYPIAI or by coactivation of other transcription factors (Kaczynski et al. 2002; Shields and Yang 1998; Zhang et al. 1998). KLF9 is also a key transcriptional regulator for uterine endometrial cell proliferation, adhesion, and differentiation, all factors that are essential during the process of pregnancy and are switched off during tumorigenesis (Pabona et al. 2012; Shimizu et al. 2010; Simmen et al. 2008, 2015). In endometrial cells, KLF9 binds to progesterone receptors and enhances transcriptional activation of the target genes (Zhang et al. 2003).
Down-regulation of KLF9 ameliorates LPS-caused acute lung injury and inflammation in mice via reducing GSDMD expression
Published in Autoimmunity, 2022
Renliang Qu, Jingjing Liu, Lili Feng, Lianbing Li, Junwei Liu, Fengnan Sun, Lin Sun
Transcription factor is a type of nucleus protein, which can regulate the target genes through binding to DNA. They are recognised as the hub of various signalling pathways and play great therapeutic capabilities in multiple inflammatory diseases [42,43]. KLF9 has been reported as transcription factor of several genes. For example, KLF9 transcriptionally modulates 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), and participates in the metastasis of cutaneous squamous cell carcinoma [43]. KLF9 has also been proven to transcriptionally inhibit matrix metalloproteinase 28 (MMP28) expression in gastric cancer [44]. To explain the underlying mechanism of KLF9 in ALI, we accessed to JASPAR database and predicted the binding between KLF9 and the GSDMD promoter. GSDMD is a member of gasdermins, consisting of two conserved domains [45]. It can be cleaved N-terminal and C-terminal domains and extensively explored in pyroptosis [46]. Kovacs et al. have verified that cleaved N-terminal of GSDMD can form the memberane pores via cooperating with cell plasma membrane. This membrane pore could further contribute to the release of inflammatory cytokines [21]. Our results manifested that KLF9 knockdown induced a decreased expression of GSDMD in both in-vivo and in-vitro models. As expected, the levels of inflammatory factors were all reduced.
Hsa_circ_0037128 aggravates high glucose-induced podocytes injury in diabetic nephropathy through mediating miR-31-5p/KLF9
Published in Autoimmunity, 2022
Rong Fang, Xiangchang Cao, Yaping Zhu, Qiming Chen
KLF9 is one of the zinc finger proteins involved in gene transcriptional regulation, and is widely involved in cell proliferation and differentiation as well as the development of organs [27]. KLF9 has been shown to be a tumour suppressor to inhibit many cancer progression, including gastric cancer [28], pancreatic cancer [29] and bladder cancer [30]. In myocardial infarction-related study, KLF9 was found to promote oxidative stress to accelerate the ischaemic injury of cardiomyocytes [31]. KLF9 played a key role in regulating liver glucose metabolism and could activate the gluconeogenic process to increase liver glucose levels, so its high expression might be an important risk factor for diabetes and fatty liver [32]. He et al. reported that lncRNA SNHG16 facilitated HG-induced podocytes injury by upregulating KLF9 via sponging miR-106a [33]. In this, we confirmed that KLF9 was targeted by miR-31-5p and hsa_circ_0037128 sponged miR-31-5p to increase KLF9 expression. The rescue experiment results suggested that KLF9 overexpression reversed miR-31-5p-mediated podocytes injury inhibition under the condition of HG, confirming that miR-31-5p targeted KLF9 to regulate DN progression.
KLF16 suppresses human glioma cell proliferation and tumourigenicity by targeting TFAM
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Xiangrong Chen, Shun Li, Yumin Ke, Shukai Wu, Tianzao Huang, Weipeng Hu, Huangde Fu, Xieli Guo
Krüppel-like factor (KLF) members, including KLFs 1–17, are zinc finger-containing transcription factors that play crucial roles in the regulation of differentiation and development as well as biological processes central to the development of malignancies [7,8]. Numerous evidence indicates a significant role for this family of transcription factors in carcinogenesis, acting as oncogenes and/or tumour suppressors under distinct cellular contexts [7,8]. Typically, KLF5 promotes proliferation of human breast, bladder and pancreatic cancer cells [9–11]. KLF6 is frequently lost in many cancers by somatic mutation, loss of heterozygosity or promoter methylation [12–14]. KLF4 suppresses tumour growth in multiple cancers, including gastric, colorectal, hepatocellular and lung carcinomas [15–18], but promotes cell cycle progression in pancreatic cancer [19]. Moreover, KLF9 regulates the transactivation of progesterone-responsive promoters and has been found to be downregulated in endometrial carcinoma and colorectal cancer [20–23], suggesting that KLF9 downregulation might be linked to cancer development. Therefore, a better understanding of the expression pattern and biological role of KLF9 in glioma progression may provide clues for novel targets for therapeutic intervention.