Muhammad, N. | bioRxiv Science

bioRxiv2024

Downstream-of-gene (DoG) transcripts contribute to an imbalance in the cancer cell transcriptome

Downstream-of-gene (DoG) transcripts are an emerging class of noncoding RNAs. However, it remains largely unknown how DoG RNA production is regulated and whether alterations in DoG RNA signatures exist in major cancers. Here, through transcriptomic analyses of matched tumors and non-neoplastic tissues and cancer cell lines, we reveal a comprehensive catalogue of DoG RNA signatures. Through separate lines of evidence, we support the biological importance of DoG RNAs in carcinogenesis. First, we reveal DoG RNAs are tissue-specific and differentially expressed in tumors versus paired normal tissues with their respective host genes involved in tumor promoting versus tumor suppressor pathways. Second, increased DoG RNA number and length is associated with poor patient prognosis. Third, depletion of essential enzyme Topoisomerase I in colon cancer alters RNA polymerase II chromatin engagement leading to termination defects and induction of DoG RNAs. Our results underlie the significance of DoG RNAs in diversifying the cancer transcriptome.

genomics↗

bioRxiv2020

The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations.

In non-small cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumor suppressor STK11 encoding the kinase LKB1 result in aggressive tumors prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant (KL) cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analyzed tumor metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards an activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KL mutant tumors. KL cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2). GFPT2 inhibition selectively reduced KL cell growth in culture and xenografts. Our results define a new metabolic vulnerability in KL tumors and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.

cancer biology↗