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Last update 08 May 2025

SMYD2

Last update 08 May 2025

Basic Info

Synonyms

Histone methyltransferase SMYD2, HSKM-B, KMT3C

+ [6]

Introduction

Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. Specifically trimethylates histone H3 'Lys-4' (H3K4me3) in vivo. The activity requires interaction with HSP90alpha. Shows even higher methyltransferase activity on p53/TP53. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates RB1 at 'Lys-860'.

Drugs associated with SMYD2

LLY-507

Target

SMYD2

Mechanism

SMYD2 inhibitors

Active Org.

Eli Lilly & Co.

Originator Org.

Eli Lilly & Co.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

BAY-598

Target

SMYD2

Mechanism

SMYD2 inhibitors

Active Org.

Bayer AG

Originator Org.

Bayer AG

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

A-893

Target

SMYD2

Mechanism

SMYD2 inhibitors

Active Org.

AbbVie, Inc.

Originator Org.

AbbVie, Inc.

Active Indication

Lung Cancer

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with SMYD2

100 Translational Medicine associated with SMYD2

0 Patents (Medical) associated with SMYD2

186

Literatures (Medical) associated with SMYD2

01 Apr 2025·Cell Death & Differentiation

A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment

Article

Author: Tuo, Hang ; Liu, Qingguang ; Guo, Yixian ; Wang, Yufeng ; Wang, Liang ; Zhu, Yifeng ; Liu, Runkun ; Yin, Guozhi ; Yang, Wei

Hypoxic microenvironment plays a critical role in solid tumor growth, metastasis and angiogenesis. Hypoxia-inducible factors (HIFs), which are canonical transcription factors in response to hypoxia, are stabilized under hypoxia and coordinate the process of hypoxia-induced gene expression, leading to cancer progression. Increasing evidence has uncovered that long noncoding RNAs (lncRNAs), which are closely associated with cancer, play crucial roles in hypoxia-mediated HCC progression, while the mechanisms are largely unknown. Here, we identified SZT2-AS1 as a novel lncRNA in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis both in vitro and in vivo. And SZT2-AS1 also mediated the hypoxia-induced HCC progression. Clinical data indicated that SZT2-AS1 level was substantially increased in HCC and closely associated with poor clinical outcomes, acting as an independent prognostic predictor. Mechanistically, SZT2-AS1 recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer, and it was required for the occupancy of HIF-1 to hypoxia response elements (HREs) and HIF target gene transcription. In addition, SZT2-AS1 was required for hypoxia-induced histone trimethylation (H3K4me3 and H3K36me3) at HREs. Through recruiting methyltransferase SMYD2, SZT2-AS1 promoted trimethylation of H3K4 and H3K36 in HCC cells. Taken together, our results uncovered a lncRNA-involved positive feedback mechanism under hypoxia and established the clinical value of SZT2-AS1 in prognosis and as a potential therapeutic target in HCC.

01 Oct 2024·Biochimica et Biophysica Acta (BBA) - General Subjects

Targeting SMYD2 promotes ferroptosis and impacts the progression of pancreatic cancer through the c-Myc/NCOA4 axis-mediated ferritinophagy

Article

Author: Yu, Wentao ; Liu, Xinrong ; Tan, Juan ; Zhan, Han ; Jiang, Yan ; Liu, Yang ; Liao, Shan ; Yuan, Bowen

BACKGROUNDPancreatic cancer (PC) is characterized by a poor prognosis and limited treatment options. Ferroptosis plays an important role in cancer, SET and MYND domain-containing protein 2 (SMYD2) is widely expressed in various cancers. However, the role of SMYD2 in regulating ferroptosis in PC remains unexplored. This study aimed to investigate the role of SMYD2 in mediating ferroptosis and its mechanistic implications in PC progression.METHODSThe levels of SMYD2, c-Myc, and NCOA4 were assessed in PC tissues, and peritumoral tissues. SMYD2 expression was further analyzed in human PC cell lines. In BxPC3 cells, the expression of c-Myc, NCOA4, autophagy-related proteins, and mitochondrial morphology, was evaluated following transfection with si-SMYD2 and treatment with autophagy inhibitors and ferroptosis inhibitors. Ferroptosis levels were quantified using flow cytometry and ELISA assays. RNA immunoprecipitation was conducted to elucidate the interaction between c-Myc and NCOA4 mRNA. A xenograft mouse model was constructed to validate the impact of SMYD2 knockdown on PC growth.RESULTSSMYD2 and c-Myc were found to be highly expressed in PC tissues, while NCOA4 showed reduced expression. Among the PC cell lines studied, BxPC3 cells exhibited the highest SMYD2 expression. SMYD2 knockdown led to decreased c-Myc levels, increased NCOA4 expression, reduced autophagy-related protein expression, mitochondrial shrinkage, and heightened ferroptosis levels. Additionally, an interaction between c-Myc and NCOA4 was identified. In vivo, SMYD2 knockdown inhibited tumor growth.CONCLUSIONSTargeting SMYD2 inhibits PC progression by promoting ferritinophagy-dependent ferroptosis through the c-Myc/NCOA4 axis. These findings provide insights into potential diagnostic and therapeutic strategies for PC.

01 Oct 2024·Molecular Biotechnology

SMYD2 Imparts Gemcitabine Resistance to Pancreatic Adenocarcinoma Cells by Upregulating EVI2A

Article

Author: Tang, Xiaolei ; Jin, Lei ; Zou, Junwei ; Qian, Daohai ; Huang, Yong ; Wu, Zhaoying

Although gemcitabine (GEM) is the first‑line drug for advanced pancreatic adenocarcinoma (PAAD), the development of GEM resistance severely limits the effectiveness of this chemotherapy. This study investigated the mechanisms of ecotropic viral integration site 2 A (EVI2A) for resistance to GEM and immune evasion in PAAD. GEM resistance-related biomarkers were predicted using GEO datasets, and GEM-resistant PAAD cells were generated. EVI2A was found expressed highly in GEM-resistant PAAD cells. Gain-of-function analyses revealed that EVI2A encouraged the proliferation and motility of GEM-resistant cells and prevented apoptosis. In addition, EVI2A reduced T cell effector activation. SMYD2 was overexpressed in GEM-resistant cells, and SMYD2 enhanced H3K36me2 modification of EVI2A, thereby promoting EVI2A expression. SMYD2 reduced the sensitivity of GEM-resistant cells, which was reversed by EVI2A knockdown. SMYD2 increased the amount of M2 macrophages (co-cultured with PAAD cells) and decreased T cell effector activation (co-cultured with macrophage supernatant), and the number of M2 macrophages was decreased and T cell effectors were activated following EVI2A knockdown. Our findings indicate that EVI2A, manipulated by the SMYD2-H3K36me2 epigenetic axis, promoted GEM resistance and M2 macrophage-mediated immune evasion in PAAD. Therefore, EVI2A might represent a therapeutic target for overcoming GEM resistance and immunosuppressive environment in PAAD.

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