Identifying novel SMYD3 interactors on the trail of cancer hallmarks

Fasano, Candida; Signorile, Martina Lepore; Marco, Katia De; Forte, Giovanna; Sanese, Paola; Grossi, Valentina; Simone, Cristiano

doi:10.1016/j.csbj.2022.03.037

Cited by 9 publications

(11 citation statements)

References 126 publications

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“…Recent data from our group are consistent with the crucial role played by SLiMs in the PPI network of SET and MYND domain containing 3 (SMYD3) in different cancer study models, including BC, CRC, and other gastrointestinal tumors [ 123 , 124 ]. In the last few years, our laboratory has focused on this methyltransferase, which is overexpressed in many types of human tumors, although its oncogenic role has not been fully understood yet [ 125 ].…”

Section: Slims In Crc Molecular Networksupporting

confidence: 80%

“…Subsequently, these interactions were validated in CRC and gastric cancer cell lines. In particular, the interaction between SMYD3 and AMPK was confirmed in multiple gastrointestinal cancer cell lines (CRC, GC, hepatocellular carcinoma, pancreatic cancer), confirming the role of SMYD3 in the metabolism of gastrointestinal cancer [ 124 ].…”

Section: Slims In Crc Molecular Networkmentioning

confidence: 90%

“…Next, to gain insight into novel SMYD3 cancer-related activities, we focused on the whole-proteome distribution of the P1-P19 tripeptides and assessed the biological function of each putative SMYD3 interactor to identify the most important candidates associated with cancer hallmarks [ 124 ]. Surprisingly, this computational tripeptide screening of the human proteome allowed us to identify crucial cancer-related proteins such as mTOR, BLM, MET, AMPK, and RBL2 (p130) as novel SMYD3 interactors [ 124 ]. Subsequently, these interactions were validated in CRC and gastric cancer cell lines.…”

Section: Slims In Crc Molecular Networkmentioning

confidence: 99%

“… Schematic representation of a novel in silico methodology developed by our group to search for new interactors of an oncoprotein of interest by taking advantage of a library of SLiMs (tripeptides P1–P19) able to bind it in vitro, as identified by surface plasmon resonance (SPR) analysis [ 124 ]. Tripeptides P1–P19 are then used as in silico probes to identify human proteins containing them, which are therefore candidate interactors of the oncoprotein of interest.…”

Section: Figurementioning

confidence: 99%

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Short Linear Motifs in Colorectal Cancer Interactome and Tumorigenesis

Fasano

Grossi

Forte

et al. 2022

Cells

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Colorectal tumorigenesis is driven by alterations in genes and proteins responsible for cancer initiation, progression, and invasion. This multistage process is based on a dense network of protein–protein interactions (PPIs) that become dysregulated as a result of changes in various cell signaling effectors. PPIs in signaling and regulatory networks are known to be mediated by short linear motifs (SLiMs), which are conserved contiguous regions of 3–10 amino acids within interacting protein domains. SLiMs are the minimum sequences required for modulating cellular PPI networks. Thus, several in silico approaches have been developed to predict and analyze SLiM-mediated PPIs. In this review, we focus on emerging evidence supporting a crucial role for SLiMs in driver pathways that are disrupted in colorectal cancer (CRC) tumorigenesis and related PPI network alterations. As a result, SLiMs, along with short peptides, are attracting the interest of researchers to devise small molecules amenable to be used as novel anti-CRC targeted therapies. Overall, the characterization of SLiMs mediating crucial PPIs in CRC may foster the development of more specific combined pharmacological approaches.

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Section: Slims In Crc Molecular Networksupporting

confidence: 80%

Section: Slims In Crc Molecular Networkmentioning

confidence: 90%

Section: Slims In Crc Molecular Networkmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Short Linear Motifs in Colorectal Cancer Interactome and Tumorigenesis

Fasano

Grossi

Forte

et al. 2022

Cells

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“…In a previous study, we performed a comprehensive in silico analysis to cluster all potential SMYD3-interacting proteins identified by screening the human proteome for a library of rare tripeptides, based on their involvement in cancer hallmarks. This approach led to the identification of new SMYD3 interactors involved in processes related to cancer hallmarks [ 18 , 19 ]. Recent studies on SMYD3 oncogenic role also revealed that it can be crucial for unperturbed cell division by promoting phase transition and allowing cancer cells to bypass cell cycle arrest signals [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The novel SMYD3 inhibitor EM127 impairs DNA repair response to chemotherapy-induced DNA damage and reverses cancer chemoresistance

Sanese,

De Marco,

Lepore Signorile

et al. 2024

J Exp Clin Cancer Res

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Background SMYD3 has been found implicated in cancer progression. Its overexpression correlates with cancer growth and invasion, especially in gastrointestinal tumors. SMYD3 transactivates multiple oncogenic mechanisms, favoring cancer development. Moreover, it was recently shown that SMYD3 is required for DNA restoration by promoting homologous recombination (HR) repair. Methods In cellulo and in vivo models were employed to investigate the role of SMYD3 in cancer chemoresistance. Analyses of SMYD3-KO cells, drug-resistant cancer cell lines, patients’ residual gastric or rectal tumors that were resected after neoadjuvant therapy and mice models were performed. In addition, the novel SMYD3 covalent inhibitor EM127 was used to evaluate the impact of manipulating SMYD3 activity on the sensitization of cancer cell lines, tumorspheres and cancer murine models to chemotherapeutics (CHTs). Results Here we report that SMYD3 mediates cancer cell sensitivity to CHTs. Indeed, cancer cells lacking SMYD3 functions showed increased responsiveness to CHTs, while restoring its expression promoted chemoresistance. Specifically, SMYD3 is essential for the repair of CHT-induced double-strand breaks as it methylates the upstream sensor ATM and allows HR cascade propagation through CHK2 and p53 phosphorylation, thereby promoting cancer cell survival. SMYD3 inhibition with the novel compound EM127 showed a synergistic effect with CHTs in colorectal, gastric, and breast cancer cells, tumorspheres, and preclinical colorectal cancer models. Conclusions Overall, our results show that targeting SMYD3 may be an effective therapeutic strategy to overcome chemoresistance.

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