PITX1 plays essential functions in cancer

Abstract

PITX1, also known as the pituitary homeobox 1 gene, has emerged as a key regulator in animal growth and development, attracting significant research attention. Recent investigations have revealed the implication of dysregulated PITX1 expression in tumorigenesis, highlighting its involvement in cancer development. Notably, PITX1 interacts with p53 and exerts control over crucial cellular processes including cell cycle progression, apoptosis, and chemotherapy resistance. Its influence extends to various tumors, such as esophageal, colorectal, gastric, and liver cancer, contributing to tumor progression and metastasis. Despite its significance, a comprehensive review examining PITX1's role in oncology remains lacking. This review aims to address this gap by providing a comprehensive overview of PITX1 in different cancer types, with a particular focus on its clinicopathological significance.

Keywords: PITX1; apoptosis; cancer; noncoding RNA; stem cell.

Figure 1

Different roles of PITX1 and its corresponding target proteins in tumors. PITX1 has been reported to play different roles in tumor proliferation, chemotherapy resistance, and apoptosis by activating various downstream effector factors.

Figure 2

PITX1 acts as a core gene that regulates the p53 signaling pathway. E2F1 as upstream of PITX1 can upregulate PITX1 expression levels by directly binding to its proximal promoter region, thereby promoting the PITX1-p53-p21 signaling pathway to cause cell cycle arrest. The mutation/deletion of Rb determines the stimulation of proliferative gene E2F1, including the ability to activate p27^kip1 and Pin1, which can directly inhibit the translation of cyclin E and CDK2, leading to cell cycle arrest. Pin1 can bind PITX1 to phosphorylated SF1, and SF-1 S203 site phosphorylation cooperates with Pin1 to increase SF-1-PITX1 interactions to promote downstream genes, but SF-1 S203 site phosphorylation is regulated by ERK1/2.

Figure 3

PTP1B dephosphorylates and promotes the degradation of PITX1 via the proteasome pathway. As upstream of PITX1, PTP1B is directly involved in inhibiting the expression of PITX1, as shown in the magnification of the dashed circle area, PTP1B can dephosphorylate the 160, 175 and 179 sites of PITX1, making PITX1 unstable and degraded through the proteasome pathway, so that PITX1 cannot promote RASAL1-induced RAS inactivation and initiation of the p53 signaling pathway. Therefore, overexpression of PTP1B can inhibit PITX1-mediated cell cycle arrest and promote tumor cell survival.

Figure 4

PITX1 regulates noncoding RNAs. PITX1, as the upstream of STAT3, can directly inhibit the transcriptional activity of STAT3, and then inhibit LINC00662-mediated EMT and metastasis in tumor cells. LINC00662 can be encapsulated by exosomes and then secreted extracellularly to be captured by macrophages, LINC00662 can promote the transformation of macrophages into tumor-associated macrophages (TAM), and promote the transcription and translation of inflammatory factor CCL22 in macrophages, macrophages secrete CCL22 outside the cell to be received by tumor cells, thereby promoting the proliferation and metastasis of tumor cells, and overexpression of PITX1 can inhibit this process. In the upper left corner of the image are other noncoding RNAs that can be involved in regulating PITX1.