Mechanistic and functional extrapolation of SET and MYND domain-containing protein 2 to pancreatic cancer

Table 1 Major SET and MYND domain-containing protein 2 nonhistone substrates

Substrate	Methylation site	Methylation effect	Affected pathways	Role of substrates in PDAC	Ref.
ALK	K1451; K1455; K1610	Promotes EML4-ALK phosphorylation and NSCLC cell growth	PI3K/AKT; JAK/STAT; RTK/Ras	ALK rearrangement-positive cancer correlates with better response to chemotherapy	[28,96]
β-catenin	K133	Promotes β-catenin nuclear translocation	Wnt/β-catenin/TCF	Mediates EMT; promotes cell proliferation, migration, and invasion	[48,97]
BMPR2	Kinase domain	Stimulates BMPR2 kinase activity; SMAD1/5 phosphorylation; BMP pathway activation	BMP	Promotes tumor growth via GRB2/PI3K/AKT pathway	[98,99]
ERα	K266	Suppresses ERα target gene activation	PI3K/AKT; MAPK-ERK	ERα expression correlates with tumor progression; endocrine therapies	[100,101]
EZH2	K307	Promotes EZH2 stability; cell proliferation; EMT;invasion in BC	RB-E2F	Linked to an aggressive phenotype	[102,103]
HSP90AB1	K531; K574	Enhances dimerization; chaperone complex formation of HSP90AB1; promotes cancer cell proliferation	PI3K/AKT	Targeting HSP90 decreases GEM chemoresistance	[25,104]
MAPKAPK3	K355	Promotes pancreatic ductal adenocarcinoma	RTK/Ras; MAPK-ERK	Interacts with HSP27; mediates gemcitabine toxicity	[16]
p53	K370	Inhibits p53 and p53-mediated transcriptional regulation	p53	p53 methylation correlates with aggressive tumors; poor prognosis	[16,22]
PARP1	K528	Enhances poly (ADP-ribosyl) ation enzymatic activity; promotes apoptotic escape of cancer cells	Base excision repair	Promotes tumorigenesis and resistance	[26,105]
PTEN	K313	Inactivates PTEN; promotes BC cell proliferation	PI3K-AKT	Loss of PTEN enhances activation of PI3K-AKT; NF-κB and MYC; promotes tumor cell growth and survival	[27,74]
RB	K810; K860	Enhances Ser 807/811 phosphorylation of RB1; enhances E2F transcriptional activity; cell cycle progression	RB-E2F pathway	Reduced expression of RB correlates with cancer progression	[23,76,78]
STAT3	K685	Activates and phosphorylates STAT3; promotes cell proliferation and survival in triple-negative BC	JAK2/STAT3	Suppress apoptosis via regulation of BCL-2 family; promotes tumorigenesis	[30,106]
P65	K310	Activates and phosphorylation p65; represses tumor cell apoptosis in triple-negative BC	NF-κB pathway	-	[30]

PDAC: Pancreatic ductal adenocarcinoma; MAPKAPK3: Mitogen-activated protein kinase activated protein kinase 3; RB: Retinoblastomaassociated protein; BC: Breast cancer; STAT3: Signal transducer and activator of transcription 3; BCL-2: B cell lymphoma-2.

Table 2 SET and MYND domain-containing protein 2 involvement in human cancers

Cancer type	Findings	Ref.
Acute lymphoblastic leukemia	SMYD2 overexpression; worse OS and EFS; higher WBC counts; a higher percentage of high-risk disease; prognostic factor	[38]
Bladder cancer	Higher expression of SMYD2; promotes cell cycle progression of cancer cells; methylation of RB	[23]
Breast cancer	SMYD2 overexpression; worse RFS; prognostic factor	[107]
	SMYD2 overexpression; poor survival	[30]
Cervical cancer	Higher expression of SMYD2; worse OS; advanced FIGO stage; larger tumor size; poor prognosis	[41]
Chronic lymphocytic leukemia	Higher expression of SMYD2; high WBC counts; complex karyotype; tumor progression	[108]
Clear cell renal cell carcinoma	SMYD2 overexpression; worse OS and DFS; high TNM stage; early tumor relapse	[46]
Colon cancer	SMYD2 overexpression; upregulation MDR1/P-glycoprotein; poor prognosis; enhances oxaliplatin resistance	[31]
Colorectal cancer	SMYD2 overexpression; activates the Wnt/β-catenin pathway; worse OS and DFS; worse oncologic outcomes	[36]
Esophageal squamous cell carcinoma	Higher expression of SMYD2; worse OS; enhances venous invasion; higher pT category and recurrence	[34]
Gastric cancer	SMYD2 overexpression correlates with larger tumor size; aggressive invasion; more lymph node metastasis; recurrence; poor OS	[33]
Hematopoietic leukemias	Higher expression of SMYD2; promote Wnt-β-Catenin signaling; poor OS	[39]
Hepatocellular carcinoma	SMYD2 overexpression correlates with tumor size; vascular invasion; differentiation; TNM stage; worse OS; poor prognosis	[14]
HPV-unrelated, non-multiple head and neck cancer	Higher expression of SMYD2; worse OS; prognostic biomarker	[15]
Lower-grade gliomas	Poor OS; prognostic biomarker	[109]
Lung adenocarcinoma	Overexpressed SMYD2 correlates with shorter OS and DFS; promotes proliferation, migration, and invasion of cancer cells	[13]
Non-small cell lung cancer	Overexpressed SMYD2 enhances cisplatin resistance; downregulates the p53 pathway	[32]
Ovarian clear cell carcinoma	Shorter OS and DSS; prognostic biomarker	[43]
Pancreatic cancer	SMYD2 overexpression; methylation of MAPKAPK3; enhances precancerous lesions; poor OS	[16]
Papillary thyroid carcinoma	SMYD2 overexpression correlates with PTC progression; poor prognosis and DFS; worse clinical outcomes	[40]
Renal cell tumor	Low expression of SMYD2 correlates with shorter DSS and DFS; prognostic biomarker	[45]

SMYD2: SET and MYND domain-containing protein 2; OS: Overall survival; EFS: Event-free survival; DFS: Disease-free survival; DSS: Disease-specific survival.