The AP-2 family of transcription factors: critical regulators of human development and cancer (2023)

The AP-2 family of transcription factors: critical regulators of human development and cancer

Yi-Liu Yang¹, Lin Yong Zhao^2*

¹West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Chiny

²Gastrointestinal kirurgisk klinik og gastrisk kræftlaboratorium, National Key Biotherapy Laboratory, West China Hospital, Sichuan University and Biotherapy Innovation Center, Chengdu, Kina

Abstract

The AP-2 family of transcription factors consists of DNA-binding proteins: AP-2α to AP-2ε. Members and homologues of this family are also known in frogs, fish and invertebrates. These proteins share the same central core region and the helix-span-helix dimerization motif required for DNA dimerization and binding. This family has been shown to influence the development of the face, limbs and kidneys in embryogenesis, while regulating differentiation and apoptosis. These proteins are also involved in the regulation of endocrine processes. In addition to their effects on growth and development, this family has been reported to correlate with carcinogenesis and cancer development. Currently, these families are related to ovarian, melanoma, lung, nasopharyngeal, breast, glioblastoma, neuroblastoma, colon, etc. They regulate the expression of many cancer-related genes and influence the occurrence, development, invasiveness and therapeutic response of cancers. Different levels of AP-2 expression are also associated with different survival rates. These results could bring a new idea to the diagnosis, classification, treatment and prognosis of cancer.

The AP-2 family of transcription factors (AP-2 family) includes five DNA-binding proteins: AP-2α to AP-2ε, encoded byTFAP2ADoTFAP2Eappropriate. Frogs, fish and invertebrates also have members or homologues of this family. With the exception of AP-2δ, the other four in the family are encoded by seven exons and share the same central core region and a helix-span-helix dimerization motif required for DNA dimerization and binding¹. In addition to highly similar DNA-binding and dimerizing domains with other family members, AP-2δ has a unique sequence specificity not observed in the other four proteins. This may be useful for regulating target gene activation².

The AP-2 family plays an important role in the regulation of cell differentiation and apoptosis. Found to affect body development in embryogenesis, including the formation of the face, limbs, kidneys, retina, central nervous system, and heart^3,4. Mutations or defectsTFAP2AITFAP2Blead to development errors^5,6. These genes are also involved in the regulation of endocrine processes. E.g,TFAP2Bassociated with insulin resistance and diabetes⁷, one secondTFAP2Cplays a key role in the regulation of estrogen signaling genes⁸.

In addition to their effects on cell fate and development, the AP-2 family has also been reported to be involved in tumorigenesis and cancer development. So far, this family has been found to be closely related to various cancers, including ovarian cancer, melanoma, lung cancer, nasopharyngeal cancer, breast cancer, glioblastoma, neuroblastoma, gastric cancer, colon cancer, etc.^9-17. They regulate the expression of many cancer-related genes, especially in breast cancer. In addition, they coordinate with the occurrence, development, invasiveness and therapeutic response of cancers. Different levels of AP-2 expression are also associated with different survival rates.

AP-2a

AP-2α encoded byTFAP2Aregulates cell growth and tissue differentiation. Its expression has been observed in epithelial and neural crest cell lines at the early stage of mouse embryogenesis³. MutationsTFAP2AIt has been shown to cause Branchio-oculo-facial syndrome (BOFS), a rare orofacial cleft syndrome that includes skin, ocular, renal and ectodermal abnormalities along with a characteristic facial appearance⁵.

Different levels of AP-2a expression in tumor cells have also been reported.

AP-2α overexpression has been found in ovarian, nasopharyngeal, and lung cancers, and increased expression may promote tumorigenesis and lead to worse cancer outcomes. In epithelial cells of a normal ovary, AP-2α is expressed only in the cytoplasm. However, in malignant epithelial ovarian tumors, AP-2α is expressed both in the nucleus and in the cytoplasm. The level of AP-2α expression in the testis is associated with an increased risk of death⁹. High expression of AP-2α has also been reported in nasopharyngeal carcinoma cells, which promotes tumor growth, while downregulation of AP-2α suppresses cell viability and inhibits tumor growth along with microvascular density¹⁴. Increased expression levels are also found in lung cancer, which is strongly associated with poor prognosis¹². This result is consistent with another study in whichTFAP2Aupregulates expressionKRT16, an independent prognostic predictor associated with poor survival in lung cancer¹⁸.

However, in some other cancers, AP-2α expression is reduced, which is associated with tumor progression. For example, suppressed AP-2a expression in breast cancer appears to be more common in invasive breast tumors than in ductal carcinoma in situ.¹⁹. Similarly, AP-2a expression inversely correlates with glioblastoma staging, which may suggest its direct role in glioblastoma carcinogenicity.¹¹. The association between decreased AP-2α expression and increased carcinogenicity is also seen in colon cancer cells¹⁷and gastric adenocarcinoma²⁰.

AP-2β

AP-2β plays a key role in the development of the ductus arteriosus and the shaping of the limbs²¹.TFAP2Bmutation leads to nonsyndromic patent ductus arteriosus and Char's syndrome, which is characterized by patent ductus arteriosus, facial dysmorphia, and fifth finger abnormalities^6,22. In addition, AP-2β is also involved in glucose and fat metabolism. Gene variantsTFAP2Bis associated with insulin resistance and type 2 diabetes⁷. It has also been reported to affect conditions related to obesity and intrauterine growth²³.

Similar to AP-2α, decreased or increasedTFAP2Bexpression has also been described in human cancers. Increased expression of AP-2β has been reported in lobular carcinoma in situ (LCIS) and invasive lobular carcinoma of the breast²⁴. Furthermore, AP-2β overexpression is associated with poor prognosis in lung adenocarcinoma²⁵and papillary thyroid cancer²⁶while reduced expression appears to be correlated with poor prognosis and poor outcome in neuroblastoma¹⁵and endometrial cancer²⁷.

AP-2y

Research suggests a link between AP-2γ and lung cancer. AP-2γ acts as an oncogenic factor that promotes lung cancer²⁸and plays a key role in the development of lung cancer²⁹. In addition, increased expression of AP-2γ is detected in lung cancer cells¹²which inhibit expressionGADD45BIPMAIP1, then promotes cell proliferation and motility in non-small cell lung cancer³⁰.

Interestingly, AP-2γ has been reported to have the opposite effect in breast cancer: it first delays tumor initiation but then promotes tumor progression¹³.TFAP2CIt has been shown to influence the development of the luminal cell type during mammary development and to act as a critical transcriptional regulator that maintains the luminal phenotype³¹.TFAP2Cregulates the expression of many genes in breast cancer.TFAP2Cit was first reported to induce high expressionERBB2(Her2)IESR1 (ERA)which affects the hormonal response in breast cancer cells⁸. Furthermore, research suggestsTFAP2Ccoordinates the expression of some other major target genes, includingFOXA1, WWOX, GREB1, CDH2, HPSE, IGSF11itp^32,33. Expressive levelTFAP2Cit also coordinates with the treatment response and survival rate of breast cancer patients. High expressionTFAP2Cwas reported for suppressionCD44, a gene associated with breast cancer, and leads to a higher pathologic complete response rate after neoadjuvant chemotherapy³⁴. But other research suggests overexpressionTFAP2Cis associated with a shorter survival time of more than 10 years from diagnosis³⁵.

AP-25

Research on AP-2δ iTFAP2Dthey are relatively rare. Compared to other members of the AP-2 family, AP-2δ appears to affect mammalian development in a different way. AP-2δ expression has been reported in the retina, central nervous system, and developing heart, while the neural crest, facial mesenchyme, and limbs show almost no expression⁴. AP-2δ expression in ganglion cells promotes fine-tuning of axonal growth in the developing retina³⁶. Additionally, loss of AP-2δ correlates with reduced axonal projections to the superior colliculus³⁷.

AP-2δ has also been found in prostate tissue³⁸. In addition, AP-2δ upregulation is demonstrated in the aggressive tumor phenotype of prostate cancer³⁹.

AP-2ε

Many studies of AP-2ε focus on its predictive value regarding patients' response to chemotherapy and treatment outcome for colorectal cancer. However, this issue is still controversial. Elbert's study indicates hypermethylationTFAP2Ecorrelates with resistance to chemotherapy in colorectal cancer⁴⁰while other studies show that response to chemotherapy cannot be predicted by methylation levels⁴¹. Regarding the value of predicting prognosis, there is also no consensus. Some studies show that hypermethylation is associated with a survival advantage⁴²an association with poorer overall and disease-free survival was also noted⁴³.

In addition, AP-2ε is also associated with human neuroblastoma. It has been reported that AP-2ε is involved in the regulation of the DNA damage response in neuroblastoma cells⁴⁴.

The AP-2 family of transcription factors play indispensable roles in embryogenesis, body formation, and development.TFAP2AITFAP2Bthey also participate in the regulation of endocrine processes. Furthermore, the family has been shown to be involved in tumorigenesis, development and prognosis of various human cancers. And now they are still being studied extensively for cancer in humans. Considering the influence of the AP-2 family on tumor type, therapeutic response and prognosis, especially as shown in breast and colon cancer, these studies may bring new ideas to the diagnosis, classification, treatment and prognosis of cancer. Meanwhile, there are still many controversial issues, including the predictive value of AP-2ε on patients' response to chemotherapy and colorectal cancer outcomes, to be investigated.

Confirm:

This work was supported by the Institute of Science and Technology of Sichuan Province, No. 2021YFS0111. The views expressed are those of the authors and are not necessarily those of the Department of Science and Technology of Sichuan Province. We apologize for the inability to cite all publications related to this topic due to journal space limitations.

Shortcuts:

TFAP: proteins that activate transcription factors.

KRT16: keratingen 16, type I cytokeratin

GADD45B: growth arrest gene and DNA damage induced beta

PMAIP1: phorbol 12-myristate-13-acetate-induced protein gene 1

ERBB2: V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2

Co2: human epidermal growth factor-2 receptor gene

ESR1: estrogen receptor gene 1

Era: estrogen receptor α gene

FOXA1:forkhead box A1 proteingen

WWOX:an oxidoreductase gene containing a WW domain

GRIP1:estrogen growth regulator gene in breast cancer 1

CDH2:gen N-kadheryny

HPSE:gen heparanazy

IGSF11:gen for immunoglobulinsuperfamiliemedlem 11

CD44:differentiation cluster gen 44

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