Tata-box-binding protein-associated factor 15 as a new potential marker in gastrointestinal tumors

Abstract

In this editorial, the roles of tata-box-binding protein-associated factor 15 (TAF15) in oncogenesis, tumor behavior, and as a therapeutic target in cancers in the context of gastrointestinal (GI) tumors are discussed concerning the publication by Guo et al. TAF15 is a member of the FET protein family with a comprehensive range of cellular processes. Besides, evidence has shown that TAF15 is involved in many diseases, including cancers. TAF15 contributes to carcinogenesis and tumor behavior in many tumors. Besides, its relationship with the mitogen-activated protein kinases (MAPK) signaling pathway makes TAF15 a new target for therapy. Although, the fact that there is few studies investigating the expression of TAF15 constitutes a potential limitation in GI system, the association of TAF15 expression with aggressive tumor behavior and, similar to other organ tumors, the influence of TAF15 on the MAPK signaling pathway emphasize that this protein could serve as a new molecular biomarker to predict tumor behavior and target therapeutic intervention in GI cancers. In conclusion, more studies should be performed to better understand the prognostic and therapeutic role of TAF15 in GI tumors, especially in tumors resistant to therapy.

Key Words: Gastrointestinal cancer, Tata-box-binding protein-associated factor 15, Cell proliferation, Cell migration, Prognosis

Core Tip: Recently, the role of tata-binding protein associated factor 15 (TAF15) in many diseases, including cancer, has been suggested. Current results support the hypothesis that TAF15 expression is related to aggressive behavior by contributing to many pathways that are involved in tumor progression. Although its role in prognosis has not been entirely determined in gastrointestinal cancers, the fact that increased TAF15 expression is associated with adverse clinicopathological parameters warrants further study with the aim of better understanding its role in predicting prognosis. Moreover, based on its association with the mitogen-activated protein kinases signal pathway, its significance as a therapeutic target, particularly in tumors resistant to treatment awaits investigation.

INTRODUCTION

Tata-box-binding protein-associated factor 15 (TAF15) is a type of RNA-binding protein that belongs to FET protein family[1,2]. TAF15 is a crucial regulator of RNA metabolism and plays a significant role in the normal functions of RNA[3-5]. Prior research has shown that chromosomal translocation of FET genes, including TAF15 can result in the formation of fusion oncoproteins in several types of tumors, such as sarcomas and leukemias[6-8]. Moreover, the knockdown and inhibition of TAF15 has an impact on the expression of a substantial number of genes, a considerable proportion of which are implicated in the regulation of the cell cycle and programmed cell death[3,9-11]. Multiple studies have demonstrated that TAF15 plays a role in various types of human diseases including malignancies[12-14]. The involvement of TAF15 in the cellular interactions that promotes cell proliferation and migration has been demonstrated, suggesting a role in tumor progression[15-17]. Recent studies have demonstrated that TAF15 has the ability to activate the mitogen-activated protein kinases (MAPK) signaling pathway in malignant tumors[15-17]. Moreover, the contribution of TAF15 in the drug tolerance of cancer cells has been noted[18,19]. Despite the existence of this evidence regarding the relationship of TAF15 with oncogenesis and tumor behavior, the exact role of this protein in these events and whether it can be used as a therapeutic target has not been fully elucidated.

Therefore, in this article, the activity of TAF15, a protein with a multifaceted role, in cancer and its potential as a treatment target are discussed in the context of gastrointestinal (GI) tumors[20-32].

TAF15

This protein is encoded by the TAF15 gene; this gene is located at chromosome 17q12 and was first reported in 2002 in a case of B-cell anaplastic large cell lymphoma[33]. As noted above, TAF15 is a member of the FET protein family (FUS-EWS), which contributes to cellular processes, including RNA splicing, transcription, mRNA transport, signaling, modification, translation, and preservation of genomic integrity[1,9,11]. Several evidence indicates that the suppression of the TAF15 gene with siRNA had a significant effect on the expression of a large number of genes, which are predominantly linked to cell proliferation and death[3,4]. On the other hand, the diverse localization of TAF15 at the cell surface and cytoplasm and its primary localization in the cell nucleus suggests that it has a function beyond DNA and RNA binding[34,35]. The contribution of TAF15 to the cellular stress response, cell adhesion, and migration via its regulation and interaction with numerous proteins has been demonstrated[36]. Accumulated data pointed out the contribution of TAF15 in different forms of diseases, including malignant tumors.

TAF15 IN CANCERS

Recent experimental studies in lung carcinoma cell cultures have revealed a new role for TAF15 in carcinogenesis in squamous cell carcinomas and its association with long noncoding RNAs in this process[36]. In parallel to these findings, increased expression of TAF15 is associated with a decrease in survival rates. The contribution of TAF15 in carcinogenesis by stabilizing the MAPK signaling pathway has been also observed, a finding of significant clinical relevance[16]. Additionally, in adenocarcinomas, TAF15 has been shown to participate in interleukin-6-activated epithelial-to-mesenchymal transition and invasion to facilitate metastasis[37]. The experimental inhibition of TAF15 by transcriptional intermediary factor-1γ has been demonstrated to prevent this phenomenon, further highlighting the urgent need to elucidate TAF15-related mechanisms for potential therapeutic interventions[37]. Moreover, blockade of TAF15 with an antibody is a feasible approach for enhancing the cytotoxicity of radiation in lung cancer, and this approach may lead to improved outcomes in non-small cell lung cancer patients with TAF15 overexpression[10].

In breast cancer, recruitment of TAF15 by LINC00504 stabilizes CEPB2 mRNA, which is associated with radio resistance and contributes to its overexpression. In addition, LINC00504 silencing increased radiosensitivity by blocking TAF15[17].

In melanomas, the association of TAF15 with oncogenesis and the impact of its suppression on the inhibition of tumor cell proliferation have also been documented[35].

TAF15 IN GI CANCERS

Regarding GI system, in colorectal cancer cell cultures, the interaction of long noncoding RNA blood vessel epicardial substance (BVES) antisense RNA 1 with miR-522-3p and TAF15 has been demonstrated to regulate BVES expression, which might offer a perspective for colorectal cancer treatment, but further study is needed[38]. In an elegant study, Tang et al[15] revealed significant upregulation of TAF15 in gastric cancer (GC) tumor tissues and cell lines. The overexpression of TAF15 was found to be correlated with increased tumor size, advanced pathological stage, and invasion. Importantly, the knockdown of TAF15 hindered the proliferation, migration, and invasion of tumor cells in cell culture and restrained tumor growth. Furthermore, this knockdown resulted in substantial decreases in the phosphorylation levels of RAF1, MEK, and ERK1/2, key components of the RAF1/MEK/ERK signaling, indicating the involvement of TAF15 in this pathway and suggesting that it could serve as a promising molecular diagnostic marker or therapeutic target for GC. A human antibody that recognizes a tumor-specific TAF15 antigen that inhibits tumor cell adhesion and spreading in stomach cancer, PAT-BA4, has been described[35].

In GI stromal tumors (GISTs), the influence of TAF15 expression on oncogenesis and prognosis has been analyzed in a recent report[39]. In this multidisciplinary study, the authors first discovered the significant upregulation of TAF15 in tumor tissues and cell lines. This upregulation was reflected by the overexpression of TAF15 in 31 patients with GIST and correlated with larger tumor size and high-risk stage, indicating its role in oncogenesis and tumor cell behavior. Although the number of patients was limited, these findings suggest that the TAF15 may be effective in determining the prognosis of GISTs and is worthy of further study. More interestingly, TAF15 knockdown, in addition to suppressing tumor cells and inhibiting tumor growth, also reduced the levels of phosphorylated RAF1, MEK and ERK1/2 in these cells. This observation suggested that TAF15 affects tumor cell behavior by regulating cell proliferation and migration via the RAF1/MEK/ERK signaling pathway.

These data support previous findings that TAF15 acts via the RAF1/MEK/ERK signaling in tumor progression across different tumor types and that TAF15 may be a potential therapeutic target in GI cancers, particularly in treatment-resistant tumors (Figure 1).

Figure 1 The transcription activation complex involving tata-box-binding protein-associated factor 15, and its relationship with the mitogen-activated protein kinase signaling pathway. For the recruitment of RNA polymerase II to protein coding gene promoters, a sequential addition of specific general transcription factor is required. Transcription factor (TF) IID recognizes a specific sequence, the tata-box, and binds to this motif by tata-box binding protein (TBP) assisted by TBP-associated factors. This process creates a sharp bend in the promoter DNA. TBP recruits TFIIA, then TFIIB, to this promoter. TFIIB recruits RNA polymerase II and TFIIF to the promoter. TFIIE joins to this complex and recruits TFIIH leading to unwind DNA at promoter and form the transcription bubble. The template strand of the transcription bubble engages with the RNA polymerase II active site and RNA synthesis begins. TBP-associated factor 15 shuttles between the nucleus and cytoplasm, and promotes the proliferation, migration and invasion of tumor cells via the activation of RAF1/MEK/ERK signaling pathway. MAPK: Mitogen-activated protein kinase; TF: Transcription factor; TBP: Tata-box binding protein; TAF15: Tata-box-binding protein-associated factor 15.

Furthermore, the discovery that α-AMA, an RNAPII inhibitor, is effective in reducing drug tolerance in cancer cells through TAF15 inhibition suggests that this protein may be a promising therapeutic target for preventing posttreatment relapses in solid tumors[40]. These findings indicate that a pharmacological strategy involving the use of novel chemicals that might also prevent aggressive behavior of tumor cells in patients with GI cancers by targeting TAF15.

Therefore, understanding the regulation of TAF15 is highly important considering the significant role of modifications in dysregulation of its expression, which affects malignant transformation and tumor progression in GI tumors. Moreover, new insight into its role as a distinct transcriptional regulator, together with its connection to signaling networks, especially the RAF1/MEK/ERK pathway, will facilitate the advancement of therapies for these tumors.

CONCLUSION

Beyond its involvement in gene fusions, TAF15 is a protein with a broad repertoire of influences on cancers, considering its roles in oncogenesis, tumor progression, and treatment. The expression of TAF15 in GI malignancies and its relationship with aggressive tumor cell behavior warrant further studies in larger cohorts. The association of TAF15 with progression-related clinicopathological factors and its value as an independent prognostic factor and indicator of aggressive tumor behavior in patients with GI tumors require further study. More importantly, the close relationship between TAF15 and the MAPK signaling pathway in GI cancers suggests that TAF15 may be a potential therapeutic target, especially in treatment-resistant cases.