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New Data Point to microRNA as Key to Myc's Ability to Drive Tumor Growth

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NEW YORK (GenomeWeb) – A team from Stanford University this week reported new data showing that Myc, a widely studied oncogene overexpressed in over half of all human cancers, depends on a microRNA cluster for some of its key oncogenic activity.

Specifically, Myc was found to maintain a neoplastic state by suppressing the polycistronic miR-17-92 cluster, which controls certain chromatin regulatory and survival programs. So, while some aspects of Myc-associated tumorigenesis are not regulated by miR-17-92, "two of the very basic programs in a cancer state — survival and self-renewal — are," Stanford's Dean Felsher, who led the research, told Gene Silencing News.

In the past, investigators have used mouse models overexpressing a conditional Myc transgene to demonstrate the gene's involvement in cancer. In these tumor models, Myc's inactivation suppressed cellular proliferation and angiogenesis, and induced senescence and apoptosis — all of which contribute to tumor regression. And while Myc is known to be a transcriptional regulator of a variety of genes, there has been no data indicating that any of these targets are responsible for its ability to maintain a neoplastic state.

Recent studies have shown that Myc regulates several different miRNAs, including miR-17-92, which is overexpressed in human lymphomas. Notably, miR-17-92 has also been found to cooperate with Myc to induce lymphomagenesis, and its suppression leads to lymphoma cell death.

Given this connection between Myc and the miRNA, Felsher and his team speculated that the two might be working in concert.

To explore this hypothesis, the investigators examined the expression of miRNAs known to be regulated by Myc in lymphoma cell lines, and found that when the oncogene was inactivated, all members of the miR-17-92 cluster were downregulated. A similar effect was seen in MYC-driven hepatocellular carcinoma cells.

The team then examined if the effects of sustained miR-17-92 expression could rescue the effects of MYC inactivation in lymphoma cells and, indeed, found that it prevented the induction of proliferative arrest, apoptosis, and senescence.

Looking to replicate these findings in vivo, the scientists implanted Myc-induced lym- phoma cells expressing either an empty control vector or a murine stem cell virus containing miR-17-92 into mice. Tumors were allowed to grow for two weeks, then Myc was inactivated. As expected, miR-17-92 expression prevented the induction of proliferative arrest, apoptosis, and senescence that would ordinarily occur in the absence of Myc.

The researchers next looked for genes regulated by both Myc and miR-17-92. A total of 401 were identified and divided into groups based on whether they were upregulated or downregulated.

"Among the genes upregulated by both Myc and miR-17-92, there was an enrichment of genes involved in DNA replication, repair, and cell cycle," they wrote in a paper appearing in Cancer Cell. Those downregulated, meantime, were found to have 4.6-fold more miR-17-92 binding sites in their 3' UTRs compared with upregulated genes, suggesting that they were directly regulated by miR-17-92 binding.

Felsher and his colleagues further winnowed down this list by focusing only on genes bioinformatically predicted to have at least two miR-17-92 binding sites in their 3' UTRs. Amongst the 15 genes selected, four — Sin3b, Hbp1, Suv420h1, and Btg1 — were chromatin modifiers not previously reported as targets of either the miRNA or Myc, as well as the apoptosis regulator Bim.

"Notably, all of these genes have been associated with proliferative control, senescence, and/or apoptosis," the scientists wrote in their paper, while Bim had already been identified as a target of miR-17-92.

Myc inactivation was found to induce expression of Sin3b, Hbp1, Suv420h1, and Btg1, as well as three Bim isoforms in cells lacking miR-17-92, but not ones expressing the miRNA, indicating that the genes are all regulated by MYC in a miR-17-92-dependent manner. Further study showed that Myc inactivation also controls the chromatin-regulating functions of Sin3b, Hbp1, Suv420h1, and Btg1.

With their data pointing to the suppression of Sin3b, Hbp1, Suv420h1, Btg1, and Bim as contributing to Myc's ability to maintain tumorigenesis, Felsher's team looked at the effects of knocking down the genes, alone or in combination, in Myc-induced lymphoma cells.

Following the loss of Myc, individual inhibition of the chromatin modifiers resulted in a modest block of proliferative arrest, and knocking down Bim alone reduced the induction of apoptosis, the investigators noted in their study. Knocking down all five of the genes resulted in a delay of proliferative arrest after Myc inactivation and decreased the rate of apoptosis more robustly than with Bim inhibition alone.

Taken together, these results indicate that miR-17-92's regulation of the five genes is required for proliferative arrest and apoptosis in the absence of Myc. Similar experiments showed that either miR-17-92 expression or the suppression of Sin3b, Hbp1, Suv420h1, and Btg1 prevented the induction of senescence following Myc inactivation.

Lastly, the researchers tested the effects of miR-17-92 expression and the suppression of the miRNA's target genes on tumors in vivo when Myc was inactivated and found that they prevented sustained tumor regression.

In light of these data, "we think … that this may be a self-renewal/survival switch" for Myc-driven cancer cells in which miR-17-92 is flipped on in order to suppress genes that would interfere with tumor progression, Felsher explained.

In addition to shedding light on a poorly understood aspect of cancer biology, the findings may also have therapeutic implications, he added.

Firstly, the study points to miR-17-92's potential as a target for cancers in which Myc is overexpressed, Felsher said. Secondly, the miRNA might be useful as a biomarker that can indicate whether a Myc-targeting drug is inducing tumor regression.

He stressed, however, that such applications will require additional research.

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