hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells

Saswati Karmakar, Parthasarathy Seshacharyulu, Imayavaramban Lakshmanan, Arokia P. Vaz, Seema Chugh, Yuri M. Sheinin, Sidharth Mahapatra, Surinder Kumar Batra, Moorthy Palanimuthu Ponnusamy

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Cancer stem cells (CSCs), which mediate drug resistance and disease recurrence in several cancers, are therapeutically relevant to ovarian cancer (OC), wherein approximately 80% of patients manifest with tumor recurrence. While there are several markers for ovarian CSCs (OCSCs), the mechanism for their self-renewal maintenance by unique driver/markers is poorly understood. Here, we evaluated the role of hPaf1/PD2, a core component of RNA Polymerase II-Associated Factor (PAF) complex, in self-renewal of OCSCs through marker and functional analyses, including CRISPR/Cas9-silencing of hPaf1/PD2 in OCSCs and provided a possible mechanism for maintenance of OCSCs. Expression of hPaf1/PD2 showed moderate to intense staining in 32.4% of human OC tissues, whereas 67.6% demonstrated basal expression by immunohistochemistry analysis, implying that the minor proportion of cells overexpressing hPaf1/PD2 could be putative OCSCs. Isolated OCSCs showed higher expression of hPaf1/PD2 along with established CSC and self-renewal markers. Knockdown of hPaf1/PD2 in OCSCs resulted in a significant downregulation of CSC and self-renewal markers, and impairment of in vitro tumor sphere (P < 0.05) and colony formation (P = 0.013). Co-immunoprecipitation revealed that OCT3/4 specifically interacts with hPaf1/PD2, and not with other PAF components (Ctr9, Leo1, Parafibromin) in OCSCs, suggesting a complex-independent role for hPaf1/ PD2 in OCSC maintenance. Moreover, there was a significant overexpression and co-localization of hPaf1/PD2 with OCT3/4 in OC tissues compared to normal ovary tissues. Our results indicate that hPaf1/PD2 is overexpressed in OCSCs and maintains the self-renewal of OCSCs through its interaction with OCT3/4; thus, hPaf1/PD2 may be a potential therapeutic target to overcome tumor relapse in OC.

Original languageEnglish (US)
Pages (from-to)14806-14820
Number of pages15
JournalOncotarget
Volume8
Issue number9
DOIs
StatePublished - 2017

Keywords

  • CSC
  • HPaf1/PD2
  • OCT3/4
  • Ovarian cancer
  • Self-renewal

ASJC Scopus subject areas

  • Oncology

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