BORIS: a key regulator of cancer stemness

Abstract

BORIS (CTCFL) is a DNA binding protein which is involved in tumorigenesis. Although, there are different opinions on the level of gene expression and function of BORIS in normal and cancer tissues, the results of many studies have classified BORIS as a protein belonging to cancer/testis (CT) genes, which are identified as a group of genes that are expressed normally in testis, and abnormally in various types of cancers. In testis, BORIS induces the expression of some male germ cell/testis specific genes, and plays crucial roles during spermatogenesis and production of sperm. In tumorigenesis, the role of BORIS in the expression induction of some CT genes and oncogenes, as well as increasing proliferation/viability of cancer cells has been demonstrated in many researches. In addition to cancer cells, some believe that BORIS is also expressed in normal conditions and plays a universal function in cell division and regulation of genes. The following is a comprehensive review on contradictory views on the expression pattern and biological function of BORIS in normal, as well as cancer cells/tissues, and presents some evidence that support the expression of BORIS in cancer stem cells (CSCs) and advanced stage/poorer differentiation grade of cancers. Boris is involved in the regulation of CSC cellular and molecular features such as self-renewal, chemo-resistance, tumorigenicity, sphere-forming ability, and migration capacity. Finally, the role of BORIS in regulating two important signaling pathways including Wnt/β-catenin and Notch in CSCs, and its ability in recruiting transcription factors or chromatin-remodeling proteins to induce tumorigenesis is discussed.

BORIS/CTCFL promotes a switch from a proliferative towards an invasive phenotype in melanoma cell lines

“…becomes aberrantly re-activated in various types of cancer, including melanoma (42). Here we confirm BORIS expression at the mRNA level (36,44) and demonstrate BORIS protein expression in melanoma cell lines.…”

“…Our finding that altered BORIS expression leads to large-scale changes in gene expression was expected, as BORIS is known to act as a transcriptional regulator (24,25,29,33). In addition, it reflects the numerous cellular processes that BORIS is involved in (42,53), many of which are altered during carcinogenesis. Multiple studies found that increased BORIS expression is linked to poor prognosis and more advanced stages of disease, hence BORIS being considered an oncogene (54)(55)(56)(57).…”

“…Furthermore, hypomethylation of the BORIS promoter is frequently observed in cancer cells (41,42). Besides regulation of expression via DNA methylation, increased BORIS levels have been observed upon CTCF knockdown (43).…”

Tumor‐Specific Transcripts Are Frequently Expressed in Hepatocellular Carcinoma With Clinical Implication and Potential Function

“…). Evidence shows that these cancer/testis–specific transcripts, instead of aiding nongenetic “noise” during tumorigenesis, support cell‐autonomous behavior and may serve as potential intervention targets …”

Promoter methylation, transcription, and retrotransposition of LINE-1 in colorectal adenomas and adenocarcinomas

“…It has been shown that its transcriptional activation regulates chromatin accessibility in the early mouse embryo, and it is involved in nuclear organization and cellular identity of embryonic stem cells [43,44]. Thus, the activity of LINE-1 may also be secondary to pluripotency and cancer stemness, where transcription factors and methyltransferases cooperate to establish uncontrolled proliferation ability, enhanced potential to self-renew, migration capacity, and differentiation potential into different cell types [45,46].…”