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Last update 23 Jan 2025

KLF9

Last update 23 Jan 2025

Basic Info

Synonyms

Basic transcription element-binding protein 1, BTE-binding protein 1, BTEB

+ [6]

Introduction

Transcription factor that binds to GC box promoter elements. Selectively activates mRNA synthesis from genes containing tandem repeats of GC boxes but represses genes with a single GC box. Acts as an epidermal circadian transcription factor regulating keratinocyte proliferation (PubMed:22711835).

Drugs associated with KLF9

Transcription Factor Inhibitors (Adynxx)

Target

KLF15 x KLF6 x KLF9

Mechanism

KLF15 inhibitors [+2]

Active Org.-

Originator Org.

Adynxx, Inc.

Active Indication-

Inactive Indication

Inflammatory pain [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KLF9

100 Translational Medicine associated with KLF9

0 Patents (Medical) associated with KLF9

435

Literatures (Medical) associated with KLF9

01 Feb 2025·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

GALNT6, transcriptionally inhibited by KLF9, promotes osteosarcoma progression by increasing EFEMP1 expression via O-glycosylation modification

Article

Author: Shen, Yuan ; Yuan, Quan ; Yu, Honghao ; Tong, Ziyuan

Osteosarcoma (OS) is one of the deadliest malignancies in adolescents and its treatment status and prognosis remain unsatisfactory. N-acetylgalactosamine transferase 6 (GALNT6), one of the key enzymes regulating O-glycosylation, functions vary in different types of cancer. Currently, the function of GALNT6 in OS is unclear. Our results showed that GALNT6 was highly expressed in OS tissues, and the patients with higher GALNT6 expression exhibited a lower overall survival rate than patients with lower GALNT6 expression. We constructed the GALNT6-knockdown and GALNT6-overexpression vectors based on Tet-on system and packaged lentiviral particles to modulate GALNT6 expression. GALNT6 silencing impaired OC cell growth and metastasis both in vivo and vitro. Kruppel-like factor 9 (KLF9), a transcription factor known to suppress OS progression, was found to block GALNT6 transcription by binding to its promoter. Meanwhile, GALNT6 overexpression restored the effects caused by KLF9 upregulation. GALNT6 was known to affect protein stability by O-glycosylation regulation, thus the label-free proteomics combined with co-immunoprecipitation/mass-spectrum (MS) analysis were conducted to identify the potential mechanism of GALNT6 in promoting OS progression. EGF-containing fibulin extracellular matrix protein 1 (EFEMP1), contained several O-glycosylation sites and was upregulated in GALNT6 overexpressing cells (Log₂FC = 1.3195, p = 0.0160), attracted our attention. We demonstrated that GALNT6 interacted with EFEMP1 at protein level. The O-glycosylation of EFEMP1 was increased by GALNT6 overexpression, which slowed the degradation rate of EFEMP1. EFEMP1 knockdown reversed the effects of GALNT6 overexpression. Collectively, our observations demonstrate that KLF9/GALNT6/EFEMP1 may be a promising direction for OS treatment.

01 Feb 2025·Life Sciences

Combined analysis of bulk, single-cell RNA sequencing, and spatial transcriptomics reveals the expression patterns of lipid metabolism and ferroptosis in the immune microenvironment of metabolic-associated fatty liver disease

Article

Author: Fang, Zhihao ; Liu, Changxu ; Ji, Yanchao ; Liu, Chang ; Cheng, Yue

AIMSThis study aims to identify key biomarkers associated with ferroptosis and lipid metabolism and investigate their roles in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD). It further explores interactions between these biomarkers and the immune-infiltration environment, shedding light on how ferroptosis and lipid metabolism influence immune dynamics in MAFLD.MAIN METHODSSingle-cell RNA sequencing data from liver samples were analyzed to evaluate expression variations related to ferroptosis and lipid metabolism in MAFLD patients. Gene scores were assessed to explore their impact on the immune microenvironment, particularly hepatocyte-macrophage communication. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to Bulk-RNA-Seq data to identify gene clusters associated with ferroptosis and lipid metabolism. The analyses were integrated into a risk assessment system and predictive model, with validation conducted through in vivo experiments.KEY FINDINGSIntegration of single-cell and WGCNA data identified 11 key genes linked to ferroptosis and lipid metabolism (e.g., IER5L, SOCS2, KLF9), significantly influencing the liver's immune microenvironment. The risk assessment system and predictive model achieved an AUC of 0.92 and revealed distinct immune and biological characteristics in MAFLD patients across risk levels. The expression patterns and biological roles of these genes were confirmed in in vivo studies.SIGNIFICANCEThis study establishes a strong link between ferroptosis- and lipid metabolism-related gene expression and MAFLD's complexity. It provides novel insights into disease mechanisms, supporting personalized prognosis and targeted therapeutic strategies for MAFLD patients.

01 Jan 2025·Journal of the American Society of Nephrology

Glycolysis in Peritubular Endothelial Cells and Microvascular Rarefaction in CKD

Article

Author: Zhou, Zhanmei ; Huang, Yujie ; Zhou, Hong ; Su, Cailing ; Cao, Wei ; Hou, Fan Fan ; Cong, Ansheng ; Hu, Zuoyu ; Li, Jinjin

Key Points

Peritubular endothelial cells have a hypoglycolytic metabolism in CKD.

Restoration of glycolysis in CKD peritubular endothelial cells by overexpressing 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase attenuates microvascular rarefaction and kidney fibrosis.

Strategies targeting the metabolic defect in glycolysis in peritubular endothelial cells may be effective in the treatment of CKD.

BackgroundPeritubular endothelial cell dropout leading to microvascular rarefaction is a common manifestation of CKD. The role of metabolism reprogramming in peritubular endothelial cell loss in CKD is undetermined.MethodsSingle-cell sequencing and metabolic analysis were used to characterize the metabolic profile of peritubular endothelial cells from patients with CKD and from CKD mouse models. In vivo and in vitro models demonstrated metabolic reprogramming in peritubular endothelial cells in conditions of CKD and its contribution to microvascular rarefaction.ResultsIn this study, we identified glycolysis as a top dysregulated metabolic pathway in peritubular endothelial cells from patients with CKD. Specifically, CKD peritubular endothelial cells were hypoglycolytic while displaying an antiangiogenic response with decreased proliferation and increased apoptosis. The hypoglycolytic phenotype of peritubular endothelial cells was recapitulated in CKD mouse models and in peritubular endothelial cells stimulated by hydrogen peroxide. Mechanically, oxidative stress, through activating a redox sensor kruppel-like transcription factor 9, downregulated the glycolytic activator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase expression, thereby reprogramming peritubular endothelial cells toward a hypoglycolytic phenotype. 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase overexpression in peritubular endothelial cells restored hydrogen peroxide–induced reduction in glycolysis and cellular ATP levels and enhanced the G1/S cell cycle transition, enabling peritubular endothelial cells to improve proliferation and reduce apoptosis. Consistently, restoration of peritubular endothelial cell glycolysis in CKD mice, by overexpressing endothelial Pfkfb3, reversed the antiangiogenic response in peritubular endothelial cells and protected the kidney from microvascular rarefaction and fibrosis. By contrast, suppression of glycolysis by endothelial Pfkfb3 deletion exacerbated microvascular rarefaction and fibrosis in CKD mice.ConclusionsOur study revealed a disrupted regulation of glycolysis in peritubular endothelial cells as an initiator of microvascular rarefaction in CKD. Restoration of peritubular endothelial cell glycolysis in CKD kidney improved microvascular rarefaction and ameliorated fibrotic lesions.

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