Therapeutic targeting using tumor specific peptides inhibits long non-coding RNA HOTAIR activity in ovarian and breast cancer

Ali R. Özeş, Yinu Wang, Xingyue Zong, Fang Fang, Jay Pilrose, Kenneth Nephew

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Long non-coding RNAs (lncRNAs) play key roles in human diseases, including cancer. Functional studies of the lncRNA HOTAIR (HOX transcript antisense RNA) provide compelling evidence for therapeutic targeting of HOTAIR in cancer, but targeting lncRNAs in vivo has proven to be difficult. In the current study, we describe a peptide nucleic acids (PNA)-based approach to block the ability of HOTAIR to interact with EZH2 and subsequently inhibit HOTAIR-EZH2 activity and resensitize resistant ovarian tumors to platinum. Treatment of HOTAIR-overexpressing ovarian and breast cancer cell lines with PNAs decreased invasion and increased chemotherapy sensitivity. Furthermore, the mechanism of action correlated with reduced nuclear factor-kappaB (NF-κB) activation and decreased expression of NF-κB target genes matrix metalloprotease 9 and interleukin 6. To deliver the anti-lncRNA to the acidic (pH approximately 6) tumor microenvironment, PNAs were conjugated to pH-low insertion peptide (pHLIP). Treatment of mice harboring platinum-resistant ovarian tumor xenografts with pHLIP-PNA constructs suppressed HOTAIR activity, reduced tumor formation and improved survival. This first report on pHLIP-PNA lncRNA targeting solid tumors in vivo suggests a novel cancer therapeutic approach.

Original languageEnglish (US)
Article number894
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Long Noncoding RNA
Antisense RNA
Ovarian Neoplasms
Breast Neoplasms
Peptides
Peptide Nucleic Acids
Neoplasms
Platinum
Therapeutics
Tumor Microenvironment
Metalloproteases
Heterografts
Interleukin-6
Drug Therapy
Cell Line
Survival

ASJC Scopus subject areas

  • General

Cite this

Therapeutic targeting using tumor specific peptides inhibits long non-coding RNA HOTAIR activity in ovarian and breast cancer. / Özeş, Ali R.; Wang, Yinu; Zong, Xingyue; Fang, Fang; Pilrose, Jay; Nephew, Kenneth.

In: Scientific Reports, Vol. 7, No. 1, 894, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Pilrose, Jay

AU - Nephew, Kenneth

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