Table 1.

Role and function of super-enhancer in cancer.

Cancer	Study	Mechanism	Gene	Function	Ref.
Multiple myeloma (MM)	In vitro	BRD4	RUNX1, BCL3 and FOSL2	In MM, key factors influencing the tumor state were linked to extensive enhancer regions known as super-enhancers. These regions exhibited unusually high concentrations of Bromodomain Containing 4 (BRD4) and Mediator complexes.	(20)
T-cell acute lymphoblastic leukemia (T-ALL)	Clinical and in vitro	H3K27ac	TAL1	The majority of endogenous super-enhancers in T-ALL cells were enriched with MYB and CBP, indicating that MYB likely plays a central role in initiating super-enhancer formation.	(41)
Diffuse large B cell lymphoma (DLBCL)	In vivo	BbD4	MYC and E2F	A functional analysis of genes associated with super-enhancers revealed that DLBCLs rely on OCA-B, highlighting a potential approach for identifying previously unrecognized cancer dependencies.	(42)
Erythroleukemia	In vitro	LSD1, CoREST, HDAC1, and HDAC2	GFI1	Analysis using gene set enrichment demonstrated that removing the GFI1 super-enhancer disrupted pathways driven by NCD38, which are associated with granulocyte differentiation and the CEBPA network. Conversely, it reactivated pathways suppressed by NCD38, including those involved in erythroid development, GATA1-regulated targets, and specific acute myeloid leukemia (AML) clusters, such as FAB subtype M6 and AML linked to chromosomal abnormalities associated with myelodysplastic syndromes.	(38)
Medulloblastoma	In vivo	BRD4	ALK, SMO and NTRK3, LMO1, LMO2, MYC, ETV4 and PAX5	Super-enhancers in medulloblastoma were found to regulate key genes listed in the Cancer Gene Census. These include ALK in the WNT subgroup; SMO and NTRK3 in the SHH subgroup; LMO1, LMO2, and MYC in Group 3; and ETV4 and PAX5 in Group 4.	(43)
Neuroblastoma	In vitro	cyclin-dependent kinase 7 (CDK7)	MYCN	Super-enhancers played a critical role in driving the elevated expression of oncogenic MYCN. The overexpressed MYCN protein extensively interacted with promoter and enhancer regions across the genome, including its own regulatory elements, resulting in widespread transcriptional activation.	(44)
Neuroblastoma	In vitro	MYB	LMO1	The study revealed that a polymorphism within a super-enhancer element located in the first intron of LMO1 impacts neuroblastoma susceptibility by altering GATA transcription factor binding. This, in turn, directly regulates LMO1 expression in cis, creating an oncogenic dependency in the tumor.	(45)
Glioblastoma	In vitro	MAPK/ERK	CDK6, SOX2, EGFR and BRD4	Super-enhancers were shown to influence key genes involved in glioblastoma stem cell identity, development, and therapeutic resistance. The study emphasized the connection between chromatin landscapes and gene expression profiles, revealing how super-enhancers drive the transcriptional programs that sustain glioblastoma’s aggressive and heterogeneous nature.	(46)
Small-cell lung cancer	In vitro	CDK7	MYC, SOX2, OTX2 and NFIB	The proto-oncogenes C-MYC (in GLC16 and NCI-H82 cells) and MYCN (in NCI-H69 cells), which are locally amplified, were found to be linked to extensive super-enhancers and showed significant sensitivity to THZ1 treatment.	(47)
Lung adenocarcinoma (LUAD)	Clinical and in vitro	–	PSMB5 and TOP2A	Through analysis of key super-enhancers, two unique subtypes were identified, each displaying distinct patterns of genomic alterations (like mutations and variations in copy number) and corresponding differences in clinical prognosis.	(37)
Breast cancer	In vitro	CDK7	SMAD3, TCF7, STAT3, CTCF	The constituent enhancers of super-enhancers that regulate genes in the Achilles cluster in Triple-negative breast cancer (TNBC) cells were found to be enriched with DNA-binding motifs recognized by signaling transcription factors.	(34)
Breast cancer	In vitro and in vivo	ANLN	FOXC1 and MET	A mechanism has been identified through which ANLN was upregulated in TNBC, with these findings highlighting the clinical and biological importance of the ANLN super-enhancer in the tumorigenesis of TNBC.	(40)
Oesophageal squamous cell carcinoma (OSCC)	In vitro and in vivo	CDK7	PAK4, RUNX1, DNAJB1, SREBF2 YAP1, and PAK4	Several lineage-specific master regulators in OSCC, and an integrative analysis of THZ1-sensitive and super enhancer-associated transcripts, uncovered a set of novel oncogenes in OSCC, such as PAK4, RUNX1, DNAJB1, SREBF2, and YAP1. Notably, PAK4 emerged as a potentially targetable kinase for therapeutic intervention.	(48)
Neck and nasopharyngeal squamous cell carcinoma	In vivo	BRD4, NF-κB p65	ETV6, MET, TP63 and FOSL1	Targeting super-enhancers with BET inhibitors proved to be an effective strategy for inhibiting the growth and metastasis of HNSCC, as it simultaneously eradicated cancer stem cells (CSCs) and the mitotic bulk of the tumor.	(49)
Colon cancer	In vitro	mitogen-activated protein kinase (MAPK)	BRAF	Super-enhancers specific to colon cancer were found to be linked to various oncogenic pathways, with a notable association with the MAPK pathway.	(29)
Colorectal Cancer (CRC)	Clinical and in vitro	–	IL-20RA	IL-20RA has been identified as a key regulator of oncogenic signaling and immune dynamics in CRC, driving the expression of genes that promote tumor progression, unchecked cell division, and evasion of immune surveillance.	(36)
Gastric adenocarcinoma	Clinical and in vitro	CDX2 and HNF4α	ABHD11, CLDN3 and CLDN4	Patients with gastric cancers characterized by elevated expression of genes linked to predicted super-enhancers experienced significantly worse overall survival compared to those with lower expression levels of these genes.	(50)
Hepatocellular carcinoma (HCC)	Clinical and in vitro	CDK7, BRD4, EP300, MED1	SPHK1, MYC, MYCN, SHH, and YAP1	HCC cells displayed exceptional sensitivity to super-enhancer complex disruption, primarily due to the selective inhibition of oncogenes driven by these regulatory elements.	(51)
Melanoma	In vivo	INO80	SOX10 and AXL	INO80 binding showed a substantial overlap and strong positive correlation with key enhancer and super-enhancer markers, including H3K4me1, H3K27ac, and Med1. These findings collectively indicate that INO80 directly interacts with super-enhancers to drive the expression of oncogenic genes in melanoma.	(52)
Ewing sarcoma	In vitro	cyclin D1/CDK4	EWS/FLI	The research identified a super-enhancer as a key regulator of the cyclin D1 gene (CCND1) and highlighted the selective reliance of Ewing sarcoma on CCND1 and CDK4, setting it apart from other types of cancer cell lines.	(53)
Pancreatic cancer	In vivo	KDM6A	ΔNp63, MYC, and RUNX3	Loss of KDM6A specifically promoted the development of squamous-like, metastatic pancreatic cancer in females by disrupting the COMPASS-like complex and aberrantly activating super-enhancers that regulate key oncogenes, including ΔNp63, MYC, and RUNX3.	(54)