Identification of novel class inhibitors of NSD3 methyltransferase showing a unique, bivalent binding mode in the SET domain

Kim, Sumin; Hwang, Injeoung; Kim, Suhn Hyung; Chung, Hwan Won; Ji, Mi‐Jung; Moon, Sojeong; Park, Hyun‐Mee; Hur, Wooyoung

doi:10.1111/cbdd.14249

Cited by 7 publications

(3 citation statements)

References 23 publications

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“…These studies correlate with our findings that NSD3S/MYC interaction stabilizes and activates MYC transcriptional activity. Finally, Kim et al, reported the identification of a new NSD3 inhibitor which targets the SET domain of the protein, therefore only the NSD3L isoform [86]. However, based on the understanding we have regarding the function of NSD3, particularly NSD3S, we believe that inhibitors targeting both isoforms would be more effective in blocking oncogenic programs, in a therapeutic context.…”

Section: Discussionmentioning

confidence: 99%

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

Cruz,

Vera,

Baeza

et al. 2023

Preprint

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NSD3 is a member of the NSD histone methyltransferase family of proteins. In recent years, it has been identified as a potential oncogene in certain types of cancer. NSD3 gene encodes three isoforms, the full length, a short (NSD3S) and WHISTLE isoforms. Importantly, NSD3S isoform corresponds to the N-terminal of the full-length protein, lacking the methyltransferase domain. The chromosomal location of NSD3 is frequently amplified across cancer types, such as breast, lung, colon, among others. Recently, this amplification has been correlated to a chromothripsis event, that could explain the different NSD3 alterations found in cancer. Fusion proteins containing NSD3 have also been reported, such as leukemia NSD3-NUP98, and in NUT midline carcinoma (NMC), NSD3-NUT fusion. Its role as an oncogene has been described by modulating different cancer pathways through its methyltransferase activity, or the short isoform of the protein, through protein interactions. Specifically, in this review we will focus on stating the functions that have been characterized as methyltransferase dependent, and those that have been correlated with the expression of the NSD3S isoform. Altogether, there is evidence that both isoforms of NSD3 are relevant for cancer progression, establishing NSD3 as a therapeutic target. However, further functional studies are needed to differentiate NSD3 oncogenic activity as dependent or independent of the catalytic domain of the protein, as well as the contribution of each isoform and its clinical significance in cancer progression.

show abstract

Section: Discussionmentioning

confidence: 99%

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

Cruz,

Vera,

Baeza

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…These studies correlate with our findings that NSD3S/MYC interaction stabilizes and activates MYC transcriptional activity. Finally, Kim et al reported the identification of a new NSD3 inhibitor which targets the SET domain of the protein, therefore only the NSD3L isoform [87]. However, based on the understanding we have regarding the function of NSD3, particularly NSD3S, we believe that inhibitors targeting both isoforms would be more effective in blocking oncogenic programs in a therapeutic context.…”

Section: Discussionmentioning

confidence: 99%

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

Nuñez,

Vera,

Baeza

et al. 2024

IJMS

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NSD3 (nuclear receptor-binding SET domain protein 3) is a member of the NSD histone methyltransferase family of proteins. In recent years, it has been identified as a potential oncogene in certain types of cancer. The NSD3 gene encodes three isoforms, the long version (NSD3L), a short version (NSD3S) and the WHISTLE isoforms. Importantly, the NSD3S isoform corresponds to the N-terminal region of the full-length protein, lacking the methyltransferase domain. The chromosomal location of NSD3 is frequently amplified across cancer types, such as breast, lung, and colon, among others. Recently, this amplification has been correlated to a chromothripsis event, that could explain the different NSD3 alterations found in cancer. The fusion proteins containing NSD3 have also been reported in leukemia (NSD3-NUP98), and in NUT (nuclear protein of the testis) midline carcinoma (NSD3-NUT). Its role as an oncogene has been described by modulating different cancer pathways through its methyltransferase activity, or the short isoform of the protein, through protein interactions. Specifically, in this review we will focus on the functions that have been characterized as methyltransferase dependent, and those that have been correlated with the expression of the NSD3S isoform. There is evidence that both the NSD3L and NSD3S isoforms are relevant for cancer progression, establishing NSD3 as a therapeutic target. However, further functional studies are needed to differentiate NSD3 oncogenic activity as dependent or independent of the catalytic domain of the protein, as well as the contribution of each isoform and its clinical significance in cancer progression.

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“…In addition, inhibitors of H3K36 methyltransferases could also act as potential drugs to control satellite expression in prostate cancer. H3K36 methyltransferases are known to act as cancer drug targets, and their inhibitors are under development [54][55][56]. Besides histone modifying enzymes that regulate the epigenetic state of heterochromatin, endonuclease Dicer1 is also known to control satellite transcript levels.…”

Section: Hypothesis: How To Stabilize Satellite Dna Transcription And...mentioning

confidence: 99%

Alpha Satellite DNA in Targeted Drug Therapy for Prostate Cancer

Feliciello,

Ugarković

2023

IJMS

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Prostate cancer is the most common solid cancer in men and, despite the development of many new therapies, metastatic castration-resistant prostate cancer still remains a deadly disease. Therefore, novel concepts for the treatment of metastatic prostate cancer are needed. In our opinion, the role of the non-coding part of the genome, satellite DNA in particular, has been underestimated in relation to diseases such as cancer. Here, we hypothesise that this part of the genome should be considered as a potential target for the development of new drugs. Specifically, we propose a novel concept directed at the possible treatment of metastatic prostate cancer that is mostly based on epigenetics. Namely, metastatic prostate cancer is characterized by the strongly induced transcription of alpha satellite DNA located in pericentromeric heterochromatin and, according to our hypothesis, the stable controlled transcription of satellite DNA might be important in terms of the control of disease development. This can be primarily achieved through the epigenetic regulation of pericentromeric heterochromatin by using specific enzymes as well as their activators/inhibitors that could act as potential anti-prostate cancer drugs. We believe that our concept is innovative and should be considered in the potential treatment of prostate cancer in combination with other more conventional therapies.

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Identification of novel class inhibitors of NSD3 methyltransferase showing a unique, bivalent binding mode in the SET domain

Cited by 7 publications

References 23 publications

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions

Alpha Satellite DNA in Targeted Drug Therapy for Prostate Cancer

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