The PVT1 promoter is a tumor-suppressive DNA element that is recurrently mutated in human tumors.
Major finding: The PVT1 promoter is a tumor-suppressive DNA element that is recurrently mutated in human tumors.
Mechanism: The PVT1 promoter competes with MYC for contact with PVT1 intragenic enhancers in breast cancer cells.
Impact: Regulatory regions of lncRNA genes may have lncRNA-independent roles in transcription and tumorigenesis.
PVT1 encodes an oncogenic long noncoding RNA (lncRNA) that stabilizes MYC to promote tumorigenesis, and the PVT1 locus is often amplified in breast cancer. However, PVT1 is also frequently disrupted by recurrent translocations or deletions, suggesting that it may have additional regulatory functions. Cho, Xu and colleagues used CRISPR/Cas9-mediated interference to investigate the function of PVT1. Silencing the PVT1 promoter increased expression of MYC, which is located 53 kb downstream of PVT1, to enhance breast cancer cell proliferation. Expression of the PVT1 lncRNA was not required to inhibit MYC transcription. Instead, the PVT1 promoter competed with MYC for binding to enhancers within the PVT1 locus, preventing MYC promoter firing and suppressing transcriptional elongation of the MYC oncogene, resulting in reduced cancer cell growth. Conversely, disrupting the PVT1 promoter facilitated MYC-enhancer contacts to promote MYC expression. However, these findings did not extend to all cell types; for example, in a colon cancer and a cervical cancer cell line, MYC looped to the CCAT1 enhancer instead of PVT1 intragenic enhancers, and therefore PVT1 did not disrupt MYC transcription. These findings suggest a role for the PVT1 promoter as a boundary element in breast cancer cells, preventing MYC from interacting with the PVT1 intragenic enhancers to reduce MYC expression. Consistent with this model, the PVT1 promoter controlled MYC expression in cis, only regulating the MYC promoter on the same chromosome. Further, recurrent alterations in the PVT1 promoter occurred in patients with breast cancer or lymphoma, and introducing these mutations into breast cancer cells provided a growth advantage and increased MYC expression in most clones. Taken together, these findings elucidate a lncRNA-independent tumor suppressive role for the PVT1 promoter in breast cancer and suggest that regulatory sequences in lncRNA genes may contribute to tumorigenesis.
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