2. Academic Validation
  3. Targeting the SP/KLF Transcriptional Regulatory Network Synergizes with HDAC Inhibition to Impede Progression of H3K27M Diffuse Intrinsic Pontine Glioma

Targeting the SP/KLF Transcriptional Regulatory Network Synergizes with HDAC Inhibition to Impede Progression of H3K27M Diffuse Intrinsic Pontine Glioma

  • Cancer Res. 2025 Jun 2;85(11):2100-2116. doi: 10.1158/0008-5472.CAN-24-2227.
Yu Kong # 1,  Fan Wang # 1,  Renwei Jing # 1,  Qian Zhao 1,  Xuejiao Lv 1,  Yingying Zhao 1,  Ye Yuan 1,  Xianyou Xia 1,  Yu Sun 2,  Yujie Tong 3,  Han Yan 1,  Qian Li 1,  Ting Li 1,  Lei Cao 1,  Deng Liu 1,  Dawei Huo 1,  Shao-Kai Sun 4,  Francisco Morís 5,  Yujie Tang 6,  Xudong Wu 1 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
  • 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 3 Department of Radiology, Tianjin Medical University General Hospital Tianjin, China.
  • 4 School of Medical Imaging, Tianjin Medical University, Tianjin, China.
  • 5 EntreChem SL, Vivero Ciencias de la Salud Calle Colegio, Oviedo, Spain.
  • 6 Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine Shanghai, China.
  • 7 Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
  • # Contributed equally.
PMID: 40053472 DOI: 10.1158/0008-5472.CAN-24-2227
Abstract

Diffuse intrinsic pontine gliomas (DIPG) are lethal pediatric brain tumors that frequently harbor H3K27M mutations and lack effective treatments. In this study, our epigenomic analyses uncovered an enrichment of specificity protein/Krüppel-like factor (SP/KLF) transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared with normal pontine neural progenitor cells. SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized mithramycin analog, significantly suppressed the proliferation and invasiveness of H3K27M-DIPG cells. A screen of epigenetic drugs showed that histone deacetylase inhibitors (HDACi) synergized with EC-8042 to suppress H3K27M-DIPG cell growth. Unexpectedly, HDACis activated transcriptional programs that enhanced tumor adaptability and invasiveness, an effect counteracted by EC-8042. Mechanistically, HDACi treatment enhanced chromatin accessibility to SP/KLF factors, whereas EC-8042 disrupted both the primary SP/KLF transcription regulatory network and the HDACi-induced secondary network. Consequently, the combination treatment significantly impeded tumor progression in orthotopic xenograft models. Transcriptomic profiling indicated that this combinatorial strategy induced transcriptional changes associated with improved prognosis in patients with DIPG. Thus, this study identifies a therapeutic approach for H3K27M-mutated DIPGs and sheds light on the limitations of HDACis in treating solid tumors. Significance: The SP/KLF transcriptional regulatory network is activated in H3K27M-mutated diffuse intrinsic pontine glioma and represents a promising therapeutic target in combination with HDAC inhibitors for combating these lethal pediatric brain tumors.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z