The Function and Regulation of SAPCD2 in Physiological and Oncogenic Processes

Abstract

The Suppressor APC Domain Containing 2 (SAPCD2) gene, also known by its aliases p42.3 and c9orf140, encodes a protein with an approximate molecular weight of 42.3 kDa. It was initially recognized as a cell cycle-associated protein involved in mitotic progression. Since the initial discovery of this gene, emerging evidence has suggested that its functions extend beyond that of regulating cell cycle progression to include modulation of planar polarization of cell progenitors and determination of cell fate throughout embryonic development. The underlying mechanisms driving such functions have been partially elucidated. However, the detailed mechanisms of action remain to be further characterized. The expression level of SAPCD2 is high throughout embryogenesis but is generally absent in healthy postnatal tissues, with restored expression in adult tissues being associated with various disease states. The pathological consequences of its aberrant expression have been investigated, most notably in the development of several types of cancers. The role of SAPCD2 in tumorigenesis has been supported by in vitro, in vivo, and retrospective clinical investigations and the mechanisms underlying its oncogenic function have been partially revealed. The potential of SAPCD2 as a diagnostic marker and therapeutic target of cancers have also been explored and have shown great promise. However, many questions pertaining to its oncogenic mechanisms as well as its value as a diagnostic marker and therapeutic target remain to be answered. In addition to its function as an oncogene, an involvement of SAPCD2 in other pathological processes such as inflammation has also been implicated and provides additional directions that warrant future investigation. This article reviews the current understanding of the normal cellular functions of SAPCD2 and the relevance of SAPCD2 in disease development with a primary focus on tumorigenesis. The mechanisms that regulate p43.2 expression, including the potential role of microRNAs in regulating its expression, are also reviewed. To the best of our knowledge, we are the first to comprehensively review the published findings regarding the physiological and pathological functions of this gene.

Keywords: Cancer; Cell Cycle; Cell Fate; Metastasis.; SAPCD2; p42.3.

Figure 1

Schematic structures of SAPCD2 gene, mRNA and protein. (1) Gene structure. The SAPCD2 gene is 3,814 nucleotides (nts) long. The promoter region contains four validated STAT5 binding sites. (2) mRNA structures. Splicing of the pre-mRNA transcript generate the mature mRNA transcript with protein coding region of 1,184 nts. A Kozak consensus sequence exists in the upstream of the coding region and serves as the translation initiation site. Portions of the exons 1 and 6 serve as the 5'UTRs and 3'UTRs, respectively, in the mature mRNA. The 3'UTR contains predicted targets sites of multiple miRNAs with the target site of miR-29a binding site having been validated. The 3' UTR also contains a validated lncRNA-PXN-AS1-L binding site. (3) Protein structure. The final translation product is a protein (389 aa) containing an EF-Hand domain at the N-terminus with a Coiled Coil domain at the C-terminus and two proline-rich regions. Twelve putative phosphorylation sites exist at positions 26, 29, 128, 181, 211, 217, 219, 279, 284, 350, 357, and 377 of the protein sequence. A putative metal ion-binding site involving four amino acids (Ala78, Ser 79, Tyr 81 and Arg 88) within the EF-hand domain is predicted. The highlighted region spans amino acids 1-239 and represents the region of the SAPCD2 protein that is essential for interaction with AXIN1.

Figure 2

Mechanisms of action of SAPCD2 protein in modulating normal and pathological cellular processes. (A) The function of SAPCD2 as a modulator of cellular processes. Up to date, SAPCD2 is found to function as an important modulator multiple cellular processes, including cell cycle progression, spindle orientation, epithelial mesenchymal transition, chromosomal instability, DNA damage responses, and cell differentiation. Such functions of SAPCD2 determine the important role of SAPCD2 in the physiological and pathological processes, such as embryonic development, oncogenesis and inflammation. Some of the pathways have been validated in in vitro or in vivo studies, while others are predicted have not been experimentally validated sufficiently. The net effect of SAPCD2 on a given cellular process can be thought of as the product of interactions with each individual protein, such that two adjacent inhibitory interactions indicate a net positive effect, while adjacent inhibitory and stimulatory interactions indicate a net negative effect. (B) The role of SAPCD2 in modulating the Wnt/β-catenin signaling.

Figure 3

The involvement of SAPCD2 in Tumorigenesis and the underlying mechanisms. While the figure depicts the mechanisms/pathways that have been characterized in each specific cancer type, none of the illustrated oncogenic mechanisms are necessarily cancer-type specific and mutually exclusive, and it is likely that each cancer type arises from a combination of multiple pathways.

Figure 4

Mechanisms that regulate SAPCD2 expression. SAPCD2 expression was found to be regulated via multiple pathways. One of well-characterized pathways involves coordinated interactions of transcription factors STAT5, E2H2 and β-catenin. In addition, ERK2, TNF-α and Wnt signaling pathway are found to promote SAPCD2 expression. However, the detailed mechanisms underlying these regulatory pathways need to be further defined. Two non-coding RNAs are demonstrated to regulate SAPCD2 expression at translational level, with miRNA miR-29a repressing its expression and lncRNA PXN-As1-L promoting its expression.