TABLE 2.

Upstream, downstream, and interacting genes of MYCN.

Category	Gene/target	Class	Mechanism of action	Drug/intervention	Experimental model	Outcome	References
Cooperating Effect	AURORA	Kinase	Forms complex with Aurora-A kinase to stabilize MYCN	HLB-0532259, PHA-68062	MNA-NB xenograft mouse	Significant tumor suppression	Tang et al., 2025, Boi et al., 2021
	ALK	Receptor tyrosine kinase	Dual inhibitor reduces MYCN expression	ESK44 (Phase I)	NB-1 cells	Inhibits tumor activity	Chugh et al., 2025
	MAX	Transcription factor	MYCN requires dimerization with MAX for oncogenic function	-	Primary NB tissue	Regulates oncogenic activity	Ferrucci et al. (2018)
	WDR5	Chromatin remodeler	Targets WBM/WIN sites to disrupt transcriptional complex	OICR-9429	MNA-NB cells	Synergistic growth inhibition	Han et al. (2023)
	BPTF	Chromatin remodeling factor	Interacts with N-Myc/CRC to regulate cell cycle	-	MNA-NB cells	Potential therapeutic target	Felipe et al. (2024)
	IGF2BP1	RNA-binding protein	Forms cooperative loop with MYCN	BTYNB+YM-155	MNA-NB cells	Synergistic inhibition	Hagemann et al. (2023)
	TCF4 (E2-2)	Transcription factor	Regulates FOXM1/E2F network through super-enhancers	-	Kelly cell line	Controls proliferation	Aljouda et al. (2025)
	SMARCE1	SWI/SNF complex	Regulated by MYCN via non-canonical E-box	-	MNA-NB cells	Inhibits proliferation	Hu et al. (2022)
	IRF2BP2	Transcriptional regulator	Activated by MYCN/MEIS2/HAND2 via SEs	-	MNA-NB cells	Maintains high proliferation	Chen et al. (2024a)
Upstream Regulators	P53	Tumor suppressor	Indirect MYCN suppression via p53 activation	PRIMA-1, RITA	MNA-NB cells	Delays progression	Mlakar et al. (2019)
	MDM2	E3 ubiquitin ligase	Regulates MYCN stability (p53-dependent/independent)	Nutlin-3, MI-63	TH-MYCN transgenic mice	Delays tumorigenesis	Chen et al. (2009)
	PI3K	Signaling kinase	Pathway inhibition reduces MYCN stability	CUDC-907, NVP-BEZ235	MNA-NB xenograft mouse	Induces degradation	Chanthery et al. (2012)
	AF1q	Oncoprotein	Regulates MYCN through Ras/ERK pathways	-	MNA-NB cells	Blocks cell cycle	Oskouian et al. (2024)
Promoter Regulation	CDK7/9/12	Cyclin-dependent kinases	Inhibits transcriptional elongation of MYCN	THZ1, YKL-5-124	MNA-NB xenograft mouse	Suppresses tumors	Gao et al. (2021)
	CRT	Chaperone protein	Binds MYCN promoter to inhibit transcription	Radiation	MNA-NB xenograft mouse	Promotes differentiation	Lee et al. (2019a)
	4-Oct	Transcription factor	Disruption induces caspase-2 apoptosis	-	MNA-NB cells	Reduces oncogenic transcripts	Nakatani et al. (2024)
	TFAP4	Transcription factor	Key effector of MYCN amplification	-	MNA-NB xenograft mouse	Promotes differentiation	Boboila et al. (2018)
	AHR	Nuclear receptor	Negatively regulates MYCN promoter	-	MYCN non-amplified cells and MNA-NB cells	Suppresses expression	Wu et al. (2014)
	BORIS	DNA-binding protein	Downregulation inhibits MYCN expression	-	MNA-NB xenograft mouse	Induces senescence	Rao et al. (2022)
	PP2A	Phosphatase	Dephosphorylates MYCN	ATUX-3364/8385	MNA-NB cells	Inhibits growth	Nazam et al. (2024)
Downstream (Activated)	GCL (cat)	Metabolic enzyme	MYCN activates via E-box binding (antioxidant pathway)	-	MYCN non-amplified cells and MNA-NB cells	Oxidative stress resistance	Veas-Perez de Tudela et al. (2010)
	E2F5	Transcription factor	Direct transcriptional activation by MYCN	-	MNA-NB cells	Promotes cell cycle	Liu et al. (2019)
	PHGDH	Metabolic enzyme	MYCN-driven serine metabolism	-	MNA-NB cells	Metabolic reprogramming	Arlt et al. (2021)
	MTHFD1	Metabolic enzyme	MYCN-activated folate metabolism	MTX+JQ1	MYCN non-amplified cells/MNA-NB cells/MNA-NB xenograft mouse	Therapy sensitization	Guan et al. (2024)
	INSM1	Transcription factor	Direct MYCN target	HHT	MNA-NB cells	Growth inhibition	Chen et al. (2023)
	SAGA complex	Epigenetic regulator	MYCN-dependent activity	KAT2A/B PROTAC	MNA-NB cells	Essential for MYCN	Malone et al. (2024)
Downstream (Repressed)	DKK1	Wnt inhibitor	Suppressed by MYCN	-	MNA-NB cells	Inhibits invasion	Koppen et al. (2007)
	DKK3	Wnt modulator	MYCN/miR-92-mediated suppression	Wnt agonists	MNA-NB cells	Promotes malignancy	Chen et al. (2024b)
	TFPI2	Protease inhibitor	Downregulated by MYCN	-	MNA-NB cells	Enhances invasion	Becker et al. (2008)
	SESN1	Stress-response protein	MYCN-regulated	-	MNA-NB cells	Inhibits migration	Hua et al. (2024)
	CD9	Surface glycoprotein	Transcriptional repression by MYCN/HDAC5	Vorinostat	MYCN non-amplified cells	Suppresses migration	Fabian et al. (2016)
Feedback Loops	INSM1	Transcription factor	Bidirectional: stabilizes MYCN, activated by MYCN	HHT	MNA-NB cells	Positive feedback	Chen et al., 2015,Chen et al., 2023
	PA2G4	Proliferation protein	Mutual stabilization with MYCN	WS6 analogs	MNA-NB cells	Induces apoptosis	Massudi et al. (2023)
	PLK1	Kinase	Phosphorylates SCF(Fbw7) to stabilize MYCN	-	MNA-NB cells	Enhances oncogenicity	Xiao et al. (2016)
	ALDH18A1	Metabolic enzyme	miR-29b/SP1 regulatory loop	YG1702	MNA-NB xenograft mouse	Tumor regression	Guo et al. (2020)
	SMAD9	Transcription factor	SE-mediated positive feedback with MYCN	-	MNA-NB cells	Promotes tumorigenesis	Tan et al. (2022)
	CRABP-II	Retinol-binding protein	Mutual activation with MYCN	-	MNA-NB cells	Positive feedback	Gupta et al. (2006)
	NCYM	Antisense gene	MYCN/OCT4 regulatory loop	ATRA	MNA-NB cells	Expression modulation	Kaneko et al. (2015)