Nav: Home

Making 'sense' of the 'cart before the horse' in mammalian cells.

January 28, 2019

A fusion gene is a new gene made by joining parts of two different genes. The current thought is that fusion genes can happen in cells with unstable genome when part of the DNA from one chromosome moves to another chromosome. When the fusion gene is transcribed into RNA, the product is a fusion RNA that then is translated into a fusion protein. Fusion proteins may lead to cancer development. For instance, they are found in some types of cancer such as leukemia, prostate, breast, lung and others, and are being studied for the diagnosis and treatment of these diseases.

"According to this accepted notion, fusion genes precede fusion RNA, but some studies have raised doubts that this is always the case. In particular, cancer studies have reported the presence of fusion RNA in individuals in which the corresponding fusion gene cannot be detected," said corresponding author Dr. Laising Yen, associate professor of pathology & immunology and of molecular and cellular biology at Baylor College of Medicine.

To explain these findings, about 10 years ago scientists proposed the 'cart-before-the-horse-hypothesis,' which puts forward the idea that fusion RNA can form first and then guide the rearrangement of genes to form the corresponding fusion gene. Although this process has been found in simpler organisms such as the paramecium, studies have yet to come forward showing that this proposed RNA-mediate gene rearrangements also happen in mammalian cells. Until now.

"The Yen lab works on RNA, and one of our interests is to study it in relation to cancer, ovarian and prostate cancer specifically," said first author Dr. Sachin Kumar Gupta, postdoctoral associate in pathology at Baylor College of Medicine. "In this study, we investigated whether the cart could actually be before the horse. Can a fusion RNA induce the corresponding fusion gene?"

The researchers worked with prostate cancer cell line LNCaP, which lacks the fusion gene TMPRSS2-ERG found in 50 percent of prostate cancers. To test "the cart before the horse" hypothesis, Gupta and his colleagues expressed in LNCaP cells a short fusion RNA consisting of part gene TMPRSS2 and part gene ERG. If the short fusion RNA led to the formation of the fusion gene TMPRSS2-ERG, they expected to find evidence of the newly created fused gene both in the DNA genome and in the form of the full-length fusion RNA produced from that fusion gene.

Making sense of the 'cart before the horse'


"When we expressed the sense or coding short fusion RNA, we did not detect evidence that the fusion gene had been formed," Gupta said. "We then thought, why not try the antisense fusion RNA instead?"

Antisense RNA is an RNA strand with a sequence that is complementary to the one of a sense or coding RNA. Coding RNA is the one that is involved in the translation of genetic instructions into protein. In theory, the authors explain, antisense RNAs should bind to the same genome segment sense RNA binds, just to a different DNA strand, and could mediate gene rearrangements leading to the formation of fusion genes.

"We found that if we overexpress the short fusion RNA in the antisense orientation, but not in the sense orientation, we can induce gene fusion in a tissue culture setting in three days," Yen said. "We showed this for two different fusion genes."

"We were very surprised. This is a non-coding RNA for which we have shown a new function: it can induce the formation of fusion genes. The antisense RNA, not the sense RNA, is the cart before the horse," Gupta said.

The researchers also showed that this RNA-induced gene fusion can occur in non-cancerous, normal cells. Expressing antisense fusion RNA in normal prostate epithelial cell lines resulted in the formation of the corresponding fusion gene in these cells.

"Our study suggests an early stage mechanism for the formation of cancer fusion genes that provides a new perspective in cancer development," Yen said. "We have uncovered a second way by which gene recombination can happen. We propose that this process is mediated by RNA with sequences that are similar to, and antisense to, those of the joined genes."

Cancer fusion genes are important for therapy and biomarker development. Fusion genes also have a lot to say regarding how a normal cell begins to transform into a cancer cell. Therefore, the authors explain, understanding the mechanisms of fusion gene formation could lead to the development of treatments to prevent cancer.

The researchers would next like to investigate whether RNA-mediated gene fusion also can happen in other types of cancer and explore the molecular mechanism for diagnosis and therapy.
-end-
Interested in learning all the details of this work? Read it in the Proceedings of the National Academy of Sciences.

Dr. Liming Luo at Baylor College of Medicine also contributed to this work. Financial support was provided by the National Institutes of Health (grants R01EB013584, DK56338, and CA125123), the Cancer Prevention Research Institute of Texas (grants HIHRRA RP160795, RP150578, RP160283), the Pilot Grant from Dan L Duncan Comprehensive Cancer Center and the Dunn Gulf Coast Consortium for Chemical Genomics.

Baylor College of Medicine

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Setbacks
Failure can feel lonely and final. But can we learn from failure, even reframe it, to feel more like a temporary setback? This hour, TED speakers on changing a crushing defeat into a stepping stone. Guests include entrepreneur Leticia Gasca, psychology professor Alison Ledgerwood, astronomer Phil Plait, former professional athlete Charly Haversat, and UPS training manager Jon Bowers.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".