Prospects of POLD1 in Human Cancers: A Review

Abstract

Cancer is the second leading cause of death globally, exceeded only by cardiovascular disease. Despite the introduction of several survival-prolonging treatment modalities, including targeted therapy and immunotherapy, the overall prognosis for the metastatic disease remains challenging. Therefore, the identification of new molecular biomarkers and therapeutic targets related to cancer diagnosis and prognosis is of paramount importance. DNA polymerase delta 1 (POLD1), a catalytic and proofreading subunit of the DNA polymerase δ complex, performs a crucial role in DNA replication and repair processes. Recently, germline and somatic mutations of the POLD1 gene have been acknowledged in several malignancies. Moreover, diversified POLD1 expression profiles have been reported in association with clinicopathological features in a variety of tumor types. With this review, we aim to summarize the current knowledge on the role of POLD1 in cancers. In addition, we discuss the future prospects and clinical applications of the assessment of POLD1 mutation and expression patterns in tumors.

Keywords: DNA repair; DNA replication; germline and somatic mutations; polymerase delta.

Figure 1

Regulation of POLD1 gene expression within the cell and physiological roles of POLD1 depending on its cellular localization. The figure highlights positive and negative regulators of the POLD1 promoter. Apart from well-known functions of POLD1 exhibited in the nucleus, recent studies have also noticed its role within the cytoplasm. bp, base pair; CDE/CHR, cycle-dependent element/cell cycle gene homology region; CTCF, CCCTC-binding factor; DREAM, dimerization partner, RB-like, E2F, and MuvB core complex.

Figure 2

Immunohistochemical staining against POLD1 within tissues of the human large intestine. (A,B) Represent POLD1 expression in the colon cancer tissue; (C) POLD1 expression in villous adenomas; (D) POLD1 expression in epithelial cells of normal mucosa of the large intestine, view of the transverse section of intestinal crypts. All sections were stained using immunohistochemical methods: primary antibody—rabbit anti-human antibody against POLD1 (HPA046524; Sigma-Aldrich, St. Louis, MO, USA), next—secondary antibody HRP-conjugated (ready-to-use dilution; ImmPRESS Universal reagent Anti-Mouse/Rabbit Ig, Vector Laboratories). Finally, the sections were stained in diaminobenzidine (DAB; Dako, Glostrup, Denmark) and counterstained with hematoxylin (Sigma-Aldrich, St. Louis, MO, USA). The magnification was (A,C) 200× and (B,D) 400×; particular bars are labeled in each photo.