Clinical prognostic value of the SMYD2/3 as new epigenetic biomarkers in solid cancer patients: a systematic review and meta-analysis

Razmi, Mahdieh; Yazdanpanah, Ayna; Etemad‐Moghadam, Shahroo; Alaeddini, Mojgan; Angelini, Sabrina; Eini, Leila

doi:10.1080/14737159.2022.2144235

Cited by 2 publications

(1 citation statement)

References 79 publications

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“…It has been known that SMYD2 is highly expressed and related to poor prognosis in multiple cancers including lung adenocarcinoma, 36 breast cancer, 15 and renal cell carcinoma 37 . Consistent with the previous conclusions regarding SMYD2 as a new prognostic epigenetic biomarker in solid cancer patients, 38 our findings have supplemented the role of SMDY2 in prostate cancer progression.…”

Section: Discussionsupporting

confidence: 91%

Targeting SMYD2 inhibits prostate cancer cell growth by regulating c‐Myc signaling

Wan

Zhang

et al. 2023

Molecular Carcinogenesis

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SMYD2 is a lysine histone methyl transferase involved in various cancers epigenetically via methylating histone H3K4, and H3K36. c-Myc is one of the major drivers of prostate cancer (PCa) initiation and progression. The roles of SMYD2 in PCa and the regulators of c-Myc activity in PCa are still under-researched. SMYD2 expression and survival outcomes in PCa cohorts were analyzed by bioinformatics analysis. SMYD2 protein levels were detected in PCa tissues by immunohistochemistry. SMYD2 knockdown cells were established to identify the effects of SMYD2 on cell growth in vitro and in vivo. GSEA and RNA sequencing were adopted to reconnoiter the signaling regulated by SMYD2 in PCa. The relationship between SMYD2 and c-Myc was examined by western blot analysis, qPCR, and immunohistochemistry. SMYD2 specific inhibitor-AZ505 was used to pharmacologically inhibit SMYD2 function in vitro and in vivo. SMYD2 expression increased in PCa tissues compared with benign prostate tissues and higher SMYD2 expression was associated with a higher risk of biochemical relapse after radical prostatectomy. SMYD2 knockdown inhibited the growth of PCa cells both in vitro and in vivo.Furthermore, high SMYD2 levels conduced to activated c-Myc signaling in PCa cells.Importantly, the pharmacological intervention of SMYD2 by AZ505 significantly repressed PCa cell growth both in vitro and in vivo. Our findings indicate that SMYD2 inhibition restrains PCa cell proliferation by regulating c-Myc signaling and provide evidence for the potential practice of SMYD2 targeting in the treatment of PCa.

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Section: Discussionsupporting

confidence: 91%

Targeting SMYD2 inhibits prostate cancer cell growth by regulating c‐Myc signaling

Wan

Zhang

et al. 2023

Molecular Carcinogenesis

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Structure of the SMYD2-PARP1 Complex Reveals Both Productive and Allosteric Modes of Peptide Binding

Zhang,

Alshammari,

Sobota

et al. 2024

Preprint

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Allosteric regulation allows proteins to dynamically respond to environmental cues by modulating activity at sites away from the catalytic center. Despite its importance, the SET-domain protein lysine methyltransferase superfamily has been understudied. Here, we present four crystal structures of SMYD2, a unique family member with a MYND domain. Our findings reveal a novel allosteric binding site with high conformational plasticity and promiscuity, capable of binding peptides, proteins, PEG, and small molecules. This site exhibits positive cooperativity with substrate binding, influencing catalytic activity. Mutations here significantly alter substrate affinity, changing the enzyme's kinetic profile. Specificity studies show interaction with PARP1 but not histones, suggesting targeted regulation. Interestingly, this site's function remains unaffected by active site changes, indicating unidirectional mechanisms. Our discovery provides novel insights into SMYD2's biochemical regulation and lays the foundation for broader research on allosteric control in lysine methyltransferases. Given SMYD2's role in various cancers, this work opens exciting avenues for designing specific allosteric inhibitors with reduced off-target effects.

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Clinical prognostic value of the SMYD2/3 as new epigenetic biomarkers in solid cancer patients: a systematic review and meta-analysis

Cited by 2 publications

References 79 publications

Targeting SMYD2 inhibits prostate cancer cell growth by regulating c‐Myc signaling

Targeting SMYD2 inhibits prostate cancer cell growth by regulating c‐Myc signaling

Structure of the SMYD2-PARP1 Complex Reveals Both Productive and Allosteric Modes of Peptide Binding

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