KDM4 inhibitor SD49-7 attenuates leukemia stem cell via KDM4A/MDM2/p21^CIP1 axis

Abstract

Rationale: Traditional treatments for leukemia fail to address stem cell drug resistance characterized by epigenetic mediators such as histone lysine-specific demethylase 4 (KDM4). The KDM4 family, which acts as epigenetic regulators inducing histone demethylation during the development and progression of leukemia, lacks specific molecular inhibitors. Methods: The KDM4 inhibitor, SD49-7, was synthesized and purified based on acyl hydrazone Schiff base. The interaction between SD49-7 and KDM4s was monitored in vitro by surface plasma resonance (SPR). In vitro and in vivo biological function experiments were performed to analyze apoptosis, colony-formation, proliferation, differentiation, and cell cycle in cell sub-lines and mice. Molecular mechanisms were demonstrated by RNA-seq, ChIP-seq, RT-qPCR and Western blotting. Results: We found significantly high KDM4A expression levels in several human leukemia subtypes. The knockdown of KDM4s inhibited leukemogenesis in the MLL-AF9 leukemia mouse model but did not affect the survival of normal human hematopoietic cells. We identified SD49-7 as a selective KDM4 inhibitor that impaired the progression of leukemia stem cells (LSCs) in vitro . SD49-7 suppressed leukemia development in the mouse model and patient-derived xenograft model of leukemia. Depletion of KDM4s activated the apoptosis signaling pathway by suppressing MDM2 expression via modulating H3K9me3 levels on the MDM2 promoter region. Conclusion: Our study demonstrates a unique KDM4 inhibitor for LSCs to overcome the resistance to traditional treatment and offers KDM4 inhibition as a promising strategy for resistant leukemia therapy.

Human circulating small non-coding RNA signature as a non-invasive biomarker in clinical diagnosis of acute myeloid leukaemia

“…AML is a highly heterogeneous disorder at the molecular and clinical levels that is generally caused by gradually accumulating mutations, numerous additional genetic and epigenetic abnormalities, and post-transcription and translation regulator alterations [40][41][42][43][44][45]. Due to their broad range of functions in post-translational regulation and the haematopoietic microenvironment, sncRNAs, especially miRNAs, play major roles in maintaining haematopoietic stem cell homeostasis and are well-documented in leukaemia progression, metastasis, and drug resistance [46][47][48][49].…”

The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities

“…Recently, Li et al found that SD49-7 (compound 80) was a KDM4 inhibitor with good in vitro and in vivo anti-leukemic activity. 163 Mechanistically, compound 80 administration could activate apoptosis signaling by reducing MDM2 levels by regulating the occupation of H3K9me3 levels on the MDM2 promoter region. Hybrid molecule 81 is a KDM4A inhibitor designed using a “two-component” strategy by crosslinking a 2-OG mimic KDM4A inhibitor with a methyl lysine mimic.…”

The role and prospect of lysine‐specific demethylases in cancer chemoresistance

“…216 The combination of methylstat with PI3K inhibition promoted activation of UPR, resulting in synergistic effects in enhancing apoptosis of PTEN-deficient breast cancer. 46 Recently, Li et al 190 identified SD49-7 as a small molecule inhibitor of KDM4A and KDM4C. Inhibition KDM4A and KDM4C by SD49-7 impairs the expression of MDM2 and activated p21 CIP1 , inhibiting the stemness and activating apoptosis of leukemia cells.…”