SP4 Facilitates Esophageal Squamous Cell Carcinoma Progression by Activating PHF14 Transcription and Wnt/Β-Catenin Signaling.

IF 4.1 2区 医学 Q2 CELL BIOLOGY Molecular Cancer Research Pub Date : 2024-01-02 DOI:10.1158/1541-7786.MCR-22-0835
Li Wei, Chaowei Deng, Bo Zhang, Guanghui Wang, Yan Meng, Hao Qin
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Abstract

Specificity protein 4 transcription factor (SP4), a member of the Sp/Krüppel-like family (KLF), could bind to GT and GC box promoters, and plays an essential role in transcriptional activating. Despite SP4 having been detected to be highly expressed in a variety of human tumors, its biological effect and underlying molecular mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. Our research discovered that high SP4 expression is detected in primary ESCC specimens and cell lines and is strongly associated with the ESCC tumor grade and poor prognosis. In vitro, knockdown of SP4 suppressed cell proliferation and cell-cycle progression and promoted apoptosis, whereas overexpression of SP4 did the opposite. In vivo, inhibiting SP4 expression in ESCC cells suppresses tumor growth. Subsequently, we demonstrated that SP4 acts as the transcriptional upstream of PHF14, which binds to PHF14 promoter region, thus promoting PHF14 transcription. PHF14 was also significantly expressed in patient tissues and various ESCC cell lines and its expression promoted cell proliferation and inhibited apoptosis. Moreover, knockdown of SP4 inhibited the Wnt/β-catenin signaling pathway, whereas overexpression of PHF14 eliminated the effects of SP4 knockdown in ESCC cells. These results demonstrate that SP4 activates the Wnt/β-catenin signaling pathway by driving PHF14 transcription, thereby promoting ESCC progression, which indicates that SP4 might act as a prospective prognostic indicator or therapeutic target for patients with ESCC.

Implications: This study identified SP4/PH14 axis as a new mechanism to promote the progression of ESCC, which may serve as a novel therapeutic target for patients with ESCC.

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SP4通过激活PHF14转录和Wnt/β-儿茶素信号传导促进食管鳞状细胞癌的进展。
特异性蛋白4转录因子(SP4)是Sp/Krüppel样家族(KLF)的一员,可与GT和GC盒启动子结合,在转录激活中发挥重要作用。尽管SP4已被检测在多种人类肿瘤中高表达,但其在食管鳞状细胞癌(ESCC)中的生物学作用和潜在的分子机制尚不清楚。我们的研究发现,在原发性ESCC标本和细胞系中检测到高SP4表达,并且与ESCC肿瘤分级和不良预后密切相关。在体外,敲低SP4抑制细胞增殖和细胞周期进展并促进细胞凋亡,而过表达SP4则相反。在体内,抑制ESCC细胞中SP4的表达抑制肿瘤生长。随后,我们证明SP4作为PHF14的转录上游,与PHF14启动子区结合,从而促进PHF14转录。PHF14也在患者组织和各种ESCC细胞系中显著表达,其表达促进细胞增殖并抑制细胞凋亡。此外,敲低SP4可抑制Wnt/β-catenin信号通路,而过表达PHF14可消除ESCC细胞中SP4敲低的影响。这些结果表明,SP4通过驱动PHF14转录激活Wnt/β-catenin信号通路,从而促进ESCC的进展,这表明SP4可能是ESCC患者的前瞻性预后指标或治疗靶点。意义:本研究确定SP4/PH14轴是促进ESCC进展的一种新机制,可作为ESCC患者的新治疗靶点。
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来源期刊
Molecular Cancer Research
Molecular Cancer Research 医学-细胞生物学
CiteScore
9.90
自引率
0.00%
发文量
280
审稿时长
4-8 weeks
期刊介绍: Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.
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