Halting the production of the notorious cancer-promoting protein MYC may be key to controlling aggressive tumors.
For many years, researchers have aimed to combat cancer by targeting the mutated proteins present in tumors. However, numerous cancers find ways to evade these treatments and continue their growth.
Recently, UCSF researchers believe they can disrupt the creation of a critical growth-associated protein, MYC, which is found in significantly high levels in about 70% of cancers. Unlike other potential targets for cancer treatments, MYC’s harmfulness stems largely from its sheer quantity.
A study published on February 4 in Nature Cell Biology by scientists at UC San Francisco reveals methods to reduce MYC levels. They identified another protein, known as RBM42, that drives the production of MYC in cells.
By interfering with RBM42 in pancreatic cancer cells, known for being particularly deadly, the researchers effectively halted their growth. The team now hypothesizes that new drugs could be designed to achieve the same impact in various aggressive cancers fueled by MYC. By inhibiting RBM42, these potential treatments would simultaneously impede MYC production.
“MYC is a common factor seen when cancers prove resistant to our treatments,” explained Davide Ruggero, PhD, a professor of urology at UCSF and the study’s senior author. “Now that we’ve identified the mechanisms that regulate MYC levels, we may finally have the means to inhibit it.”
Why is MYC so prevalent?
MYC was first discovered in the 1970s by UCSF Nobel Laureates Michael Bishop, MD, and Harold Varmus, MD, while they were researching virus-induced cancers. MYC is typically a regular protein, but it adopts a harmful role within cancer cells, marking a significant advancement in cancer research and therapy.
Unlike other oncogenic elements, MYC can remain unaltered, functioning normally yet being produced excessively as a means for cells to become cancerous. It is also utilized by pathologists as a microscopic indicator of rapidly proliferating tumors.
“While the importance of MYC in cancer is widely recognized, effective drugs to inhibit it have been lacking,” said Joanna Kovalski, PhD, the primary author of the study. “We chose to investigate how MYC is actually synthesized instead.”
Kovalski employed a technique called CRISPRi to discover the factors responsible for MYC synthesis in cancer cells. Surprisingly, this led to the identification of a lesser-known protein, RBM42, which had previously received little attention.
Through an analysis of genomic data from pancreatic cancer patients, Kovalski observed that RBM42 levels were high in cells with elevated MYC levels. Moreover, patients with higher counts of both RBM42 and MYC had poorer health outcomes.
Manipulating the protein assembly process
Kovalski and Ruggero sought to understand how RBM42 affected MYC production.
Similar to any protein, MYC is synthesized based on the information encoded in the MYC gene. Initially, during a process called transcription, the cell uses this code to create a template known as mRNA. Subsequently, in a process called translation, the cell’s ribosomes utilize this mRNA to produce the MYC protein.
The researchers were taken aback by their findings. When they disrupted the function of RBM42, the cancer cells continued to create MYC mRNA but ceased the production of the MYC protein. This indicated that RBM42 primarily plays a role in the latter phase: transforming mRNA into protein.
Further tests clarified this role. RBM42 modified the MYC mRNA template, enhancing its suitability for ribosomal processing. Additionally, it guided these mRNAs toward the ribosomes, which then produced vast amounts of MYC. RBM42 guaranteed MYC received priority treatment from the cell’s protein-making machinery.
“Proteins such as RBM42 and MYC are present in all cells but are usually kept in check,” Ruggero noted. “In cancer, we observed that RBM42 acted quite differently, commandeering the ribosomes to process specific mRNAs and serve the cancer’s needs.”
Eliminating MYC
In experiments conducted on cancer cells in petri dishes and later in mice, the researchers found that removing RBM42 halted MYC production and tumor growth in pancreatic cancer.
“RBM42 appears to be a critical vulnerability in some of the most aggressive forms of cancer,” Ruggero remarked.
Kovalski, Ruggero, and their colleagues at UCSF believe that small molecules could interfere with this process, acting like molecular tools to obstruct cancer’s progression.
“Controlling translation should be a priority in our cancer treatment strategies,” Kovalski expressed. “We now have a solid foundation to intervene in the aggressive cancers and potentially improve outcomes for patients.”
