| Summary: | The phosphatase and tensin homolog deleted on chromosome 10 (<i>PTEN</i>) is a well characterised tumour suppressor, playing a critical role in the maintenance of fundamental cellular processes including cell proliferation, migration, metabolism, and survival. Subtle decreases in cellular levels of PTEN result in the development and progression of cancer, hence there is tight regulation of the expression, activity, and cellular half-life of PTEN at the transcriptional, post-transcriptional, and post-translational levels. <i>PTENP1</i>, the processed pseudogene of <i>PTEN</i>, is an important transcriptional and post-transcriptional regulator of <i>PTEN. PTENP1</i> expression produces sense and antisense transcripts modulating <i>PTEN</i> expression, in conjunction with miRNAs. Due to the high sequence similarity between <i>PTEN</i> and the <i>PTENP1</i> sense transcript, the transcripts possess common miRNA binding sites with the potential for <i>PTENP1</i> to compete for the binding, or ‘sponging’, of miRNAs that would otherwise target the <i>PTEN</i> transcript. <i>PTENP1</i> therefore acts as a competitive endogenous RNA (ceRNA), competing with <i>PTEN</i> for the binding of specific miRNAs to alter the abundance of PTEN. Transcription from the antisense strand produces two functionally independent isoforms (<i>PTENP1</i>-<i>AS-α</i> and <i>PTENP1-AS-β</i>), which can regulate <i>PTEN</i> transcription. In this review, we provide an overview of the post-transcriptional regulation of <i>PTEN</i> through interaction with its pseudogene, the cellular miRNA milieu and operation of the ceRNA network. Furthermore, its importance in maintaining cellular integrity and how disruption of this <i>PTEN</i>–miRNA–<i>PTENP1</i> axis may lead to cancer but also provide novel therapeutic opportunities, is discussed. Precision targeting of <i>PTENP1</i>-miRNA mediated regulation of <i>PTEN</i> may present as a viable alternative therapy.
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