The oncogene MYC is localized in the chromosomal region 8q24.21, a region frequently amplified in many human tumors. In addition to MYC, this locus also hosts the GSDMC and CCDC26 genes as well as the lncRNA PVT1. A gain of function for all of these genes is observed in many tumors along with MYC.

In the paper by Tseng et al.1, the authors investigate whether low copy number gain of one, or more, of the genes on 8q24.21 promotes cancer. In human breast and ovarian cancers, gain of 8q24.21 is often accompanied by ERBB2/HER2 amplification2,3. Therefore, by using the MMTVneu transgenic mice, which harbor amplified Erbb2/Her2, the authors generated a series of mouse models: gain(Myc), gain(Pvt1,Ccdc26,Gsdmc) and gain(Myc,Pvt1,Ccdc26,Gsdmc). The authors observed that single supernumerary of gain(Myc) and gain(Pvt1,Ccdc26,Gsdmc) was not sufficient to promote cancer in the MMTVneu mouse model. In contrast, gain(Myc,Pvt1,Ccdc26,Gsdmc) showed shorter mammary tumor latency and increased penetrance compared to the other genotypes, suggesting that other genetic elements, not only Myc, within the 8q24.21 region, are involved in cancer progression. The authors excluded Gsdmc and Ccdc26 from this process and focused on the functional role of the lncRNA PVT1.

To elaborate their findings, the studies were expanded to human breast cancer cell lines, which harbor high copy gains of 8q24.21. Transcriptional activity of the two genes did not appear linked since knockdown of either PVT1 or MYC did not affect the mRNA expression of one another. However, cellular proliferation was decreased upon knockdown of MYC as well as PVT1 and knockdown of both MYC and PVT1 did not further reduce cellular proliferation, thus suggesting that MYC and PVT1 may act in the same pathway.

Although changes in expression of PVT1 had no effect on MYC mRNA expression, it was noted that high levels of PVT1 correlated with increased levels MYC protein and this effect appeared to be a consequence of increased stability of the MYC protein. It is well established that MYC protein degradation is promoted by phosphorylation of threonine 58 (Thr58) (Figure 1A)4. The authors speculated and observed that PVT1 protects the MYC protein from phosphorylation-mediated degradation (Figure 1B).

Figure 1
figure 1

(A) In normal cells, MYC is targeted by phosphorylation on threonine 58 (Thr58) and becomes destabilized and degraded. (B) In cancer cells, gain of 8q24 promotes the expression of MYC and PVT1. PVT1 interferes with the phosphorylation of Thr58 on MYC, which stabilizes the protein and increases its level.

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In order to further dissect the mechanism of action, Tseng et al.1 showed that MYC and PVT1 co-localize in the nucleus. Moreover, RNA immunoprecipitation of MYC supported the notion that MYC and PVT1 are indeed part of the same complex. In addition, the authors applied the CRISPR method to the MYC-driven colon cancer cell line HCT116 and generated PVT1-null cells (ΔPVT1-HCT116). In support of their findings, the ΔPVT1-HCT116 cells demonstrated reduced proliferation and impaired colony formation in soft agar, and xenograft studies showed either failed tumor formation or reduced volume compared to the parental HCT116 cells. Finally, using publically available databases, the authors found that > 97% of tumors with increased 8q24 copy number had increased copy number of both MYC and PVT1 genes.

In summary, this exciting study provides convincing data that PVT1 is an important regulatory lncRNA, which is involved in modulating the phosphorylation of MYC and cancer progression. The findings presented within this study are in line with previous reports suggesting that phosphorylation of STAT3 is regulated by a lncRNA, lnc-DC5.

While the functional investigation of lncRNAs has long focused on chromatin remodeling6, a role beyond chromatin is now emerging. The intriguing studies carried out by Tseng et al.1 suggest that several questions remain to be addressed. It would indeed be of great interest to precisely investigate how PVT1 is interfering with the phosphorylation of MYC. For instance, 1) Is there a specific domain of PVT1, which is responsible for the action7? 2) Does PVT1 form direct interactions with MYC thereby blocking the phosphorylation of Thr58? And 3) Does PVT1 interact with other proteins except MYC? By addressing these questions in future studies, it could be possible to identify regulatory sequences within PVT1. This would not only allow for better understanding of the interplay between PVT1 and MYC, but could also lead to the identification of conserved regions and RNA structures. Such structures might also be present in other lncRNAs with similar functions and serve as the basis of potentially new therapeutics to disrupt such interactions and affect cancer progression.