Pinin interacts with C-terminal binding proteins for RNA alternative splicing and epithelial cell identity of human ovarian cancer cells

Abstract

Unlike many other human solid tumors, ovarian tumors express many epithelial markers at a high level for cell growth and local invasion. The phosphoprotein Pinin plays a key role in epithelial cell identity. We showed that clinical ovarian tumors and ovarian cancer cell lines express a high level of Pinin when compared with normal ovarian tissues and immortalized normal ovarian surface epithelial cell lines. Pinin co-localized and physically interacted with transcriptional corepressor C-terminal binding proteins, CtBP1 and CtBP2, in the nuclei of cancer cells. Knockdown of Pinin in ovarian cancer cells resulted in specific reduction of CtBP1 protein expression, cell adhesion, anchorage-independent growth, and increased drug sensitivity. Whole transcriptomic comparison of next-generation RNA sequencing data between control ovarian cancer cell lines and cancer cell lines with respective knockdown of Pinin, CtBP1, and CtBP2 expression also showed reduced expression of CtBP1 mRNA in the Pinin knockdown cell lines. The Pinin knockdown cell lines shared significant overlap of differentially expressed genes and RNA splicing aberrations with CtBP1 knockdown and in a lesser degree with CtBP2 knockdown cancer cells. Hence, Pinin and CtBP are oncotargets that closely interact with each other to regulate transcription and pre-mRNA alternative splicing and promote cell adhesion and other epithelial characteristics of ovarian cancer cells.

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

“…Higher PNN mRNA and/or Pinin protein expression levels were observed in tissues from ovarian carcinoma, hepatocellular carcinoma and CRC compared to the relative matched normal mucosa tissues. In these studies, high levels of PNN and/or Pinin were also associated with poor prognosis . A role of PNN in epithelial–mesenchymal transition has been suggested.…”

“…However, more recently, studies performed also in other cancers suggested a role of PNN in prognosis and in resistance to chemotherapy . Higher PNN mRNA and/or Pinin protein expression levels were observed in tissues from ovarian carcinoma, hepatocellular carcinoma and CRC compared to the relative matched normal mucosa tissues. In these studies, high levels of PNN and/or Pinin were also associated with poor prognosis .…”

“…PNN was successively supposed to be a tumor suppressor gene in renal cell carcinomas by genetic location and CpG islands methylation analysis . However, more recently, studies performed also in other cancers suggested a role of PNN in prognosis and in resistance to chemotherapy . Higher PNN mRNA and/or Pinin protein expression levels were observed in tissues from ovarian carcinoma, hepatocellular carcinoma and CRC compared to the relative matched normal mucosa tissues.…”

“…A role of PNN in epithelial–mesenchymal transition has been suggested. Zhang et al . reported that Pinin resembles other epithelial markers such as E‐cadherin and play a role in ovarian tumorigenesis and progression.…”

The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target

“…Following these early studies, CtBP1 overexpression has been observed in a number of different cancers, including prostate (64, 68), melanomas (69), colon (70), leukemia (71–73), ovarian (74, 75), and breast cancer (76, 77), among others. In most cases CtBP1 overexpression is pro-tumorigenic.…”