Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells

Abstract

Octamer-binding transcription factor 3/4 (OCT-3/4), which is involved in the tumorigenesis of somatic cancers, has diverse functions during cancer development. Overexpression of OCT-3/4 has been detected in various human somatic tumors, indicating that OCT-3/4 activation may contribute to the development and progression of cancers. Stem cells can undergo self-renewal, pluripotency, and reprogramming with the help of at least four transcription factors, OCT-3/4, SRY box-containing gene 2 (SOX2), Krüppel-like factor 4 (KLF4), and c-MYC. Of these, OCT-3/4 plays a critical role in maintenance of undifferentiated state of embryonic stem cells (ESCs) and in production of induced pluripotent stem cells (iPSCs). Stem cells can undergo partitioning through mitosis and separate into specific cell types, three embryonic germ layers: the endoderm, the mesoderm, and the trophectoderm. It has been demonstrated that the stability of OCT-3/4 is mediated by the ubiquitin-proteasome system (UPS), which is one of the key cellular mechanisms for cellular homeostasis. The framework of the mechanism is simple, but the proteolytic machinery is complicated. Ubiquitination promotes protein degradation, and ubiquitination of OCT-3/4 leads to regulation of cellular proliferation and differentiation. Therefore, it is expected that OCT-3/4 may play a key role in proliferation and differentiation of proliferating cells.

Keywords: E3 ligase; OCT-3/4; deubiquitination; post-translational modification; stem cell; transcription factors; ubiquitination.

Figure 1

Interaction of target protein with ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs). E3s and DUBs regulate target proteins including transcription factors such as octamer-binding transcription factor 3/4 (OCT-3/4). DUBs regulate the stability of OCT-3/4. Proliferation and differentiation in cancer cells and stem cells are regulated by ubiquitination and deubiquitination systems.

Figure 2

OCT-3/4 (PDM ID: 3L1P, https://www.ncbi.nlm.nih.gov/Structure/pdb/3L1P) is regulated by different kinds of posttranslational modifications (PTMs). SUMOylation (K118), glycosylation (T228), phosphorylation (S347), ubiquitination, methylation, and acetylation of OCT-3/4 regulate the pluripotency, differentiation, and self-renewal of stem cells.

Figure 3

OCT-3/4 is also related to tumorigenesis of somatic cancers. Expression level of OCT-3/4 is related to development of cancers such as cervical cancer, colon cancer, and breast cancer, as well as testicular germ cell tumors, drug-resistant cells, and undifferentiated tumor-initiating cells; accordingly, OCT-3/4 can be a novel therapeutic target for the treatment of cancers.