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 journalArticle

12 Citations (Scopus)

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 - Jan 1 2017

Fingerprint

Neoplastic Stem Cells
Ovarian Neoplasms
Maintenance
Recurrence
Neoplasms
Clustered Regularly Interspaced Short Palindromic Repeats
RNA Polymerase II
Immunoprecipitation
Drug Resistance
Ovary
Down-Regulation
Immunohistochemistry
Staining and Labeling

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Karmakar, S., Seshacharyulu, P., Lakshmanan, I., Vaz, A. P., Chugh, S., Sheinin, Y. M., ... Palanimuthu Ponnusamy, M. (2017). hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells. Oncotarget, 8(9), 14806-14820. https://doi.org/10.18632/oncotarget.14775

hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells. / Karmakar, Saswati; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban; Vaz, Arokia P.; Chugh, Seema; Sheinin, Yuri M.; Mahapatra, Sidharth; Batra, Surinder Kumar; Palanimuthu Ponnusamy, Moorthy.

In: Oncotarget, Vol. 8, No. 9, 01.01.2017, p. 14806-14820.

Research output: Contribution to journalArticle

Karmakar, S, Seshacharyulu, P, Lakshmanan, I, Vaz, AP, Chugh, S, Sheinin, YM, Mahapatra, S, Batra, SK & Palanimuthu Ponnusamy, M 2017, 'hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells', Oncotarget, vol. 8, no. 9, pp. 14806-14820. https://doi.org/10.18632/oncotarget.14775
Karmakar S, Seshacharyulu P, Lakshmanan I, Vaz AP, Chugh S, Sheinin YM et al. hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells. Oncotarget. 2017 Jan 1;8(9):14806-14820. https://doi.org/10.18632/oncotarget.14775
Karmakar, Saswati ; Seshacharyulu, Parthasarathy ; Lakshmanan, Imayavaramban ; Vaz, Arokia P. ; Chugh, Seema ; Sheinin, Yuri M. ; Mahapatra, Sidharth ; Batra, Surinder Kumar ; Palanimuthu Ponnusamy, Moorthy. / hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells. In: Oncotarget. 2017 ; Vol. 8, No. 9. pp. 14806-14820.
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