Long-range regulation of tumor suppressor genes plays key role in cancer

Enhancers are regulatory elements that play an important role in cancer. Researchers from Rutgers Cancer Institute of New Jersey, the state's only National Cancer Institute-designated Comprehensive Cancer Center, identified a novel enhancer.

It interacts with a tumor suppressor gene and explored its involvement in normal T-cell development as well as in T-cell acute lymphoblastic leukemia (T-ALL).

Daniel Herranz, PharmD, PhD, resident researcher at Rutgers Cancer Institute and assistant professor of Pharmacology at Rutgers University, is senior author of the work and shares more about the findings published in Blood Cancer Discovery, a journal of the American Association for Cancer Research.

Why is this topic important to explore?

Most of the human genome does not contain coding genes, and for decades it was referred to as "junk DNA" or "dark matter." Thus, it was believed that only mutations in coding genes, either oncogenes or tumor suppressor genes (TSGs), could lead to cancer development.

However, in the last few years it has been discovered that this "junk DNA" is not useless, and that there are many regions that, even if they don't codify for a gene themselves, they participate in the regulation of other genes.

These regions are called "enhancers" and, as the name indicates, they promote the expression of their target gene. Indeed, we had previously identified an enhancer of the oncogene MYC as critically involved in T-cell development and transformation (Herranz, et al., Nat Med, 2014).

Describe the work and tell us what the team discovered

Here, following on our years-long interest in enhancer regions, we have identified a novel enhancer that regulates the expression of the tumor suppressor gene PTEN, which we named PE for PTEN Enhancer.

Using a variety of chromosome conformation techniques, genome editing and novel mouse models with germinal or conditional deletion of this PE enhancer, we demonstrate that this region promotes the expression of PTEN in normal T-cells and T-ALL, such that loss of this region results in decreased PTEN levels, which translate into faster leukemia development and progression.

Moreover, we identified recurrent deletions in human T-ALL patients encompassing this enhancer, and these patients show reduced levels of PTEN, underscoring its relevance in the pathogenesis of this disease.

What are the implications of these findings?

Most of the enhancer regions implicated in cancer development to date regulate oncogenes such as MYC.

However, whether long-range transcriptional regulation of TSGs by enhancers plays any relevant role in tumorigenesis remained largely unknown. PTEN is the second most frequently mutated TSG in cancer, only surpassed by p53 itself.

As such, our findings have major implications as they demonstrate that long-range regulation of TSGs plays an important role in cancer.

Our results pave the way for the discovery of additional enhancer regions regulating PTEN that might be important in a wide range of other malignancies where PTEN is typically lost or mutated and, more broadly, lay the groundwork for the systematic analysis of enhancer regions controlling other TSGs across different cancer types.

Source:
Journal reference:

Tottone, L., et al. (2020) A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia. Blood Cancer Discovery. doi.org/10.1158/2643-3230.BCD-20-0201.

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