Embodiments disclosed herein concern compositions and methods for treating a condition characterized by overexpression of long non-coding RNA HOTAIR. In certain embodiments, synthetic polynucleotide analogs capable of hybridizing with a target sequence domain of HOTAIR are provided. The synthetic polynucleotide analogs can be formulated into a pharmaceutical composition for treating a subject having or at risk of having a condition characterized by HOTAIR overexpression. In certain embodiments, the pharmaceutical composition can resensitize a subject to a chemotherapeutic agent. Other embodiments concern uses for HOTAIR-targeting synthetic polynucleotide analogs, including methods for determining HOTAIR expression in a sample.