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Review
. 2023 Oct 12;15(20):4954.
doi: 10.3390/cancers15204954.

PTEN, PTENP1, microRNAs, and ceRNA Networks: Precision Targeting in Cancer Therapeutics

Glena Travis  1 , Eileen M McGowan  1   2 , Ann M Simpson  3 , Deborah J Marsh  4 , Najah T Nassif  1
Affiliations
Review

PTEN, PTENP1, microRNAs, and ceRNA Networks: Precision Targeting in Cancer Therapeutics

Glena Travis et al. Cancers (Basel). .

Abstract

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) 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. PTENP1, the processed pseudogene of PTEN, is an important transcriptional and post-transcriptional regulator of PTEN. PTENP1 expression produces sense and antisense transcripts modulating PTEN expression, in conjunction with miRNAs. Due to the high sequence similarity between PTEN and the PTENP1 sense transcript, the transcripts possess common miRNA binding sites with the potential for PTENP1 to compete for the binding, or 'sponging', of miRNAs that would otherwise target the PTEN transcript. PTENP1 therefore acts as a competitive endogenous RNA (ceRNA), competing with PTEN for the binding of specific miRNAs to alter the abundance of PTEN. Transcription from the antisense strand produces two functionally independent isoforms (PTENP1-AS-α and PTENP1-AS-β), which can regulate PTEN transcription. In this review, we provide an overview of the post-transcriptional regulation of PTEN 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 PTEN-miRNA-PTENP1 axis may lead to cancer but also provide novel therapeutic opportunities, is discussed. Precision targeting of PTENP1-miRNA mediated regulation of PTEN may present as a viable alternative therapy.

Keywords: PTEN; PTENP1; ceRNA networks; microRNAs; precision therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The multifaceted roles of the PTENP1-S sense transcript and the two isoforms of the PTENP1 antisense transcript (PTENP1-AS-α and PTENP1-AS-β) in the transcriptional and post-transcriptional regulation of PTEN expression. PTENP1-AS-α binds to the 5’-UTR of PTEN-associated transcripts and localises to the PTEN promoter region, where epigenetic modifiers are recruited, resulting in the transcriptional repression of PTEN. The PTENP1-AS-β transcript binds to the PTENP1 sense transcript, which lacks a poly-A tail, and provides stability to this transcript. The PTENP1-sense and PTENP1-AS-β transcripts form a complex that is exported into the cytoplasm, allowing the PTENP1 sense transcript to act as a miRNA sponge to post-transcriptionally regulate PTEN (due to the high sequence similarity of the two transcripts) through participation in the ceRNA network (created with Biorender.Com).
Figure 2
Figure 2
Cancer therapeutic opportunities to restore PTEN levels through the manipulation of PTEN mRNA, PTENP1, miRNAs, and long non-coding RNAs. MicroRNAs can be therapeutic targets in cancer by increasing or decreasing (shown by the ↑ and ↓arrows, respectively) the levels of either the tumour suppressor microRNAs or oncomiRs, respectively. PTEN mRNA levels can be increased through overexpression or the delivery of PTEN mRNA into cells to bring the level to a precancerous level and reverse the cancer phenotype. Increasing the levels of PTENP1-S through overexpression after delivery into cancer cells leads to ‘sponging’ of miRNAs that would normally bind and repress PTEN, leading to increased PTEN levels and reversal of the cancer phenotype. Furthermore, increasing or decreasing the levels of other known lncRNAs that participate in the PTEN–miRNA–PTENP1 ceRNA network to positively modulate tumour suppressor miRNAs or negatively modulate oncomiRs is another approach as a cancer therapeutic (created with BioRender.com).
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Grants and funding

This research received no external funding.
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