TABLE 3.

Epigenetic modulation of MYCN.

Regulation type	Subcategory	Target/molecule	Mechanism of action	Intervention drug/method	Experimental model	Effect	References
Ubiquitination	-	Aurora kinase	Alters N-Myc/SCF(FbxW7) interaction	MLN8054/8237	MNA-NB cells	Inhibits N-Myc degradation	Brockmann et al. (2013)
	-	KLHL37	Blocks N-Myc/FBXW7 interaction	RTA-408	Patient-derived NB cells and MNA-NB xenograft mouse	Stabilizes N-Myc protein	Xiang et al. (2025)
	-	HSP70	Steric hindrance of STUB1-mediated ubiquitination	HSP70 allosteric inhibitors	MNA-NB cells	Promotes K416/K419 degradation	Xu et al. (2024)
	-	USP7 (HAUSP)	Mediates N-Myc deubiquitination	P22077	MNA-NB xenograft mouse	Suppresses tumor growth	Tavana et al. (2016)
Acetylation	-	BRD4	Recognizes acetylated histones to drive MYCN transcription	JQ1	MNA-NB cells	Downregulates MYCN expression	Puissant et al. (2013)
	-	HDAC3	Cooperates with MYCN to repress GRHL1	SAHA	MNA-NB cells	Induces apoptosis	Fabian et al. (2014)
	-	Runx1t1	Modulates chromatin accessibility via LSD1-CoREST3-HDAC	-	TH-MYCN transgenic mice	Suppresses NB initiation	Murray et al. (2024)
	-	p300	Maintains N-Myc stability via K199 acetylation	p300 inhibitors	MNA-NB cells	Reduces MYCN protein levels	Cheng et al. (2023)
		KAT2A	Acetylation enhances MYCN stability	KAT2A PROTAC degraders	MNA-NB cells and MNA-NB xenograft mouse	Decreases MYCN protein	Liu et al. (2025)
Methylation	-	PRMT1	Catalyzes asymmetric dimethylation	PRMT1 knockout	MYCN non-amplified cells	G2/M phase arrest	Eberhardt et al. (2016)
	-	PRMT5	Cooperates with E2F1 to regulate splicing factors	GSK3203591/JNJ-64619178	TH-MYCN transgenic mice	Induces apoptosis and extends survival	Bojko et al. (2024)
	-	EHMT2 (G9a)	Highly expressed in MNA-NB, suppresses differentiation	UNC0638/UNC0642	MNA-NB cells	Selectively induces apoptosis	Bellamy et al. (2020)
	-	KDM4A-C	MYCN-induced, maintains demethylated state	KDM4 inhibitors	MNA-NB cells	Promotes differentiation and apoptosis	Abu-Zaid et al. (2024)
	-	METTL3/METTL14/WTAP	Mediates m6A modification of HOX genes	METTL3 inhibitors	Neural crest models	Induces DNA damage and differentiation	Thombare et al. (2024)
	-	SNRPD3	MYCN/PRMT5 enhances its methylation	P-RMT5 inhibitors	MNA-NB cells	Inhibits BIRC5 aberrant splicing	Salib et al. (2024)
	-	KDM1A (LSD1)	Co-localizes with MYCN at CDKN1A/p21 promoter	TCP	MNA-NB cells	Restores tumor suppressor expression	Amente et al. (2015)
Non-coding RNA	lncRNA	CASC15-003	Regulates MYCN stability via USP36	USP36 inhibitors	MNA-NB xenograft mouse	Suppresses tumor growth	Juvvuna et al. (2021)
	lncRNA	MILIP	MYCN-activated, promotes DNA repair	MILIP inhibitors	MNA-NB cells	Enhances cisplatin efficacy	Wang et al. (2022b)
	lncRNA	NEAT1	Competes with miR-873-5p to upregulate MYCN	CARM1 inhibitors	MNA-NB cells	Inhibits proliferation and migration	Hu et al. (2025)
	miRNA	let-7 family	MYCN-repressed, targets MYCN mRNA	MX25-1	MNA-NB cells	Degrades MYCN mRNA	Liu et al. (2022b)
	miRNA	miR-204	Directly targets MYCN 3′UTR	REP-204	NCG mouse models	Inhibits tumor metastasis	Chiangjong et al. (2024)
	miRNA	miR-21	Downregulated by MYCN (no direct phenotype)	-	MNA-NB cells	No significant effect	Buechner et al. (2011a)
	miRNA	LIN28B	Activated by MYCN promoter	-	Human fetal sympathetic ganglia	Promotes invasion and migration	Tao et al. (2020)
	siRNA	siMYCN	Silences MYCN mRNA	Folate-nanoparticle delivery	Bone metastasis model	Suppresses metastasis	Zhu et al. (2013)
	siRNA	MYCN-A3	Alkylates MYCN transcript (pyrrole-imidazole polyamide)	Intravenous injection	MNA-NB xenograft mouse	Inhibits tumor progression	Yoda et al. (2019a)
	siRNA	Pt-191-PIP	Targets MYCN DNA sequence	IV (in vitro only)	Kelly cell line	Reduces cell viability	Obata et al. (2023)
Targeted Therapy	-	ZD55-shMYCN	Oncolytic adenovirus + gene silencing	Intratumoral injection	MNA-NB cells	Induces apoptosis and oncolysis	Li et al. (2015)
	-	BGA002	Antisense PNA oligonucleotide targeting MYCN	Systemic administration	MNA-NB cells	Triggers mitochondrial damage	Montemurro et al. (2019)