Understanding the link between central precocious puberty and MKRN3 gene could provide a new avenue for managing non-small cell lung cancers.
A team of researchers from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences have discovered a novel gene that drives the progression of human lung cancer.
Considering how essential breathing is to life, it is unsurprising that lung cancer is the leading cause of cancer-related death in the world. About 85 per cent of all lung cancer cases are non-small cell lung cancers (NSCLCs). Currently, while treatment options like protein inhibitors and immunotherapy have improved survival in some patients, the prognosis for NSCLCs remain poor.
Some NSCLCs are driven by mutations in the KRAS gene and individuals with such mutations are often unresponsive to treatment with tyrosine kinase inhibitors and so, have a poor survival outlook. Of course, there have been inhibitors approved for the KRASG12C mutant to deal with NSCLC, however, a general strategy that targets all KRAS mutants remains to be known.
Less than a decade ago, it was found that central precocious puberty (CPP), or the early onset of puberty in boys and girls, is largely caused by mutations in the MKRN3 gene. Interestingly, CPP is epidemiologically linked to various diseases in adulthood, including cancers. Individuals with CPP have shown an increased risk of invasive cancers such as lung cancers.
To find out if CPP-associated MKRN3 gene is mutated in human cancers, Dr Wang Yuexiang and colleagues looked into The Cancer Genome Atlas (TCGA) Pan-Cancer genomic data sets. Notably, they observed that MKRN3 abnormalities are more common in human NSCLC samples with cancer-causing KRAS mutations.
By using genetic, functional, mouse models, and mechanistic data, the researchers now recognise the CPP-associated MKRN3 gene as a valid tumour suppressor in NSLC. They have uncovered MKRN3 tumour suppressing mechanism and emphasised MKRN3-PABPC1 protein deregulation as an important pathway in lung cancer progression.
When they restored MKRN3 in MKRN3-inactivated NSCLC cells, MKRN3 was able to suspend tumour growth and proliferation in vitro and in vivo. In mice models, mice without functional MKRN3 were susceptible to urethane-induced lung cancer, and lung cell-specific knockout of MKRN3 sped up NSCLC tumorigenesis in vivo. Furthermore, a mass spectrometry-based proteomics screen identified PABPC1 as a major substrate for MKRN3, where the inactivation of MKRN3 leads to lung cancer proliferation and progression through PABPC1-mediated global protein synthesis. Therefore, it might be worthwhile to target MKRN3 deficiency as a potential treatment strategy for KRAS-mutant NSCLC.
Given the link between early-onset puberty and cancer risk, these findings reveal that biological mechanisms of central precocious puberty are indeed relevant to tumorigenesis, which may aid in the development of anti-cancer drugs. [APBN]
Source: Li et al. (2021). E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non–small cell lung cancer. Journal of Experimental Medicine, 218(8), e20210151.