Table 2 Cancer-specific implications of SMYD3
From: SMYD3: a regulator of epigenetic and signaling pathways in cancer
Cancer type | Clinicopathologic associations | Cancer cell phenotypes | Molecular mechanisms |
|---|---|---|---|
Colorectal cancer (CRC) | SMYD3 expression correlates with: incidence of CRC [36], advanced T stage [38], and lower survival rates [38] | Cellular Proliferation and EMT [36] | JAK/STAT pathway and MYC/Ctnnb1 oncogenes [36] |
| Â | Lower SMYD3 promoter methylation levels correlate with lymph node metastasis and stage III/IV disease [37] | Â | Â |
| Â | SMYD3 is identified as an independent prognostic factor in CRC [38] | Â | Â |
Hepatocellular carcinoma (HCC) | SMYD3 expression correlates with: HCC development [36], shorter overall and disease-free survival after chemotherapy [36, 39], and poor prognosis in stage I-II disease [2] | Cellular proliferation (via regulation of CcnA2, CcnE1, CcnD1, Pcna, Igfbp1, CK2, MMP2) [2, 36] | Â HSP90a enhances SMYD3-mediated H3K4 methylation [23] |
| Â | Â | EMT (via regulation of Snai1, Snai2, Twist, Zeb1, SOX4, Fn1, Vimentin, Timp1, Mmp2, Mmp7, Mmp9, and Mmp14) [23, 36] | Â Transcriptional elongation (via recruitment of helicase and RNA polymerase II) [23] |
|  | SMYD3 is an independent prognostic factor of 5-year HCC relapse [2] |  |  SMYD3-HBX Interactions (activation of AP-1, PI3K/AKT and ERK signaling, C-MYC) [40, 41, 43] |
Breast cancer (BC) | Decreased SMYD3 mRNA expression is associated with improved relapse-free survival [44] | EMT (via regulation of TGF-beta controlled EMT-specific transcription factors such as SMAD3) [47] | |
| Â | Â | Â | Â Tri-methylation and activation of HER2 [30] |
| Â | Â | Cell proliferation (via expression changes in cell cycle genes (Cyclin D1, CDK2, and CDK4) and apoptosis genes (such as p53/p21 and Bcl-2/BAX ) [51] | Â Methylation of VEGFR1 leading to its enhanced kinase activity [26] |
| Â | Â | Â | Â Transcriptional coactivation of ER, and enhancement of ER-mediated transcription [29] |
Gastric carcinoma (GC) | SMYD3 expression correlates with: larger size of primary tumor, greater lymph node metastasis, and advanced TNM stage [52], and Poorer 5-year survival [52] | Cell proliferation (via increased G2/M progression mediated by ATM-CHK2/p53) [58] | Â Beta-catenin/TCF4/SMYD3-mediated ASCL2 activation [53] |
| Â | Â | Â | -SMYD3-STAT3 interaction [54] |
Cervical cancer | Â | Cell proliferation [59] | Â |
Prostate cancer | Â SMYD3, and EZH2 independently predict prostate cancer patient outcome [60] | Â | Â SMYD3-mediated H4K20 tri-methylation, and repression, of CCND2 [61] |
| Â | Â | Â | Â SMYD3-mediated binding and regulation of AR [63] |
Pancreatic cancer/lung cancer | SMYD3 expression correlates with: tumor size, TNM stage, perineural invasion, lymph node metastasis in pancreatic adenocarcinoma, and shorter overall survival [65] | Â | Â SMYD3-mediated mono-, di-, or tri-methylation of MAP3K2 [27] |
| Â | SMYD3 was identified as an independent prognostic indicator for overall survival [65] | Â | Â SMYD3-dependent MAP3K2 tri-methylation blocks MAP3K2 from inactivation by PP2A [27] |
Non-small cell lung cancer (NSCLC) | SMYD3 expression correlates with: never-smoked history, advanced pathologic stage, larger tumor size, presence of lymphovascular invasion, pleural invasion, distant metastasis [70], and poorer disease free-survival and overall survival [70] | Cell proliferation (Via induction of apoptosis via regulation of Bim, Bak, Bax, BCL-2, and Bcl-xl [70] | Â SMYD3-mediated cisplatin resistance [72] |
| Â | Â | EMT (via regulation of MMP-2 and MMP-9) [70] | Â HSP90 serves as a co-factor in SMYD3-mediated transcription of Met [71] |
Ovarian cancer |  SMYD3 expression increases from normal ovaries → fallopian tubes → primary cancer lesions → metastatic lesions [72] | EMT (via regulation of E-cadherin and vimentin [72] |  SMYD3 and UBE2R2 interaction promotes ubiquitination/degradation of p53 [72] |
| Â | Â SMYD3 expression correlates with increased risk of lymph node metastasis and poor overall survival [72] | Cellular adhesion (SMYD3-mediated binding to ITGB6 and ITGAM) [75] | Â Increased BIRC3 expression via SMYD3-mediated H3K4 tri-methylation [73] |
| Â | Â | Â | Â Decreased CDKN2A expression via SMYD3-mediated H4K20 tri-methylation [73] |
Esophageal cancer | SMYD3 expression correlates with increased risk of lymph node metastasis and poor overall survival [76] | Â | Â SMYD3-mediated binding to, and transcription regulation of, EZR and LOXL2 [76] |
| Â | SMYD3 is an independent prognostic factor for poor overall survival [76] | Â | Â SMYD3-EZR-AS1 interaction enhances EZR transcription [77] |
| Â | Patients with the SMYD3 3/3 VNTR genotype had a 3-fold increase of esophageal squamous cell carcinoma when smoking, but no increase in non-smokers [78] | Â | Â |
Bladder cancer | SMYD3 expression correlates with:Â tumor stage, lymph node metastasis, and poorer progression-free survival [81, 84], shorter overall survival [81, 84] | Cell proliferation (Increased apoptosis via regulation of Cyclin D1, CDK4, Cyclin E1, CDK2, p21, and p27 [81] | Â Possible feedback loop of SMYD3/IGF-1R/AKT/E2F-1 [81] |
| Â | Â | Autophagy activation (via BCLAF1 interaction) [84] | Â SMYD3 interacts with, and modulates expression of, BCLAF1 via H3K4 di-/tri-methylation [84] |
Malignant Glioma | SMYD3 expression correlates with:Â poorer overall survival [87] | Cell proliferation (possibly via regulation of p53) [87] | Â |
| Â | SMYD3 expression inversely correlates with:Â p53 expression [87] | Â | Â |