The SMYD3 methyltransferase in lung adenocarcinoma
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Lung cancer is the leading cause of cancer deaths worldwide, with more than 1.4 million deaths every year. Adenocarcinoma is a subtype of Non-Small Cell Lung Cancer (NSCLC) that comprises almost 50% of all lung cancers and results in over 500,000 deaths worldwide each year. Most often, tumors are discovered as locally advanced or metastatic disease, and despite improvements in molecular diagnosis and targeted therapies, the average 5-year survival rate for lung adenocarcinoma is less than 15%.
 
 
 
 
 
 The role of proteins such as kinases (enzymes that add phosphate groups onto other proteins) in cancer cells is well established, but little is known about how other enzymatic activities such as protein methyltransferases (which add methyl groups –CH3 onto other proteins) affect the expansion of tumor cells. Methylation of histone proteins, which cover the DNA of cells, is a principal regulatory mechanism involved in fundamental processes such as gene transcription. Less appreciated is the fact that methyltransferases also have non-histone protein targets. A central hypothesis to be tested in this proposal is that specific lysine methyltransferases regulate the function of non-histone proteins important for tumor development in vivo. Specifically, this proposal focuses on the SMYD3 lysine methyltransferase as a potential critical regulator of cancer cell proliferation and survival. Evidence in the literature and our preliminary results suggest that loss of SMYD3 function reduces the growth of tumor cell populations while overexpression of SMYD3 increases tumorigenic potential. Furthermore, SMYD3 levels are up-regulated in a large number of human tumors, including tumors with activating mutations in the RAS oncogene. Thus, SMYD3 may have oncogenic potential. 
 
 
 
 
 
 My primary objective is to test if loss of SMYD3 function inhibits cancer development in mouse models of lung adenocarcinoma, a deadly cancer in which the RAS pathway is often activated. My second goal is to elucidate the mechanisms of SMYD3 action. In preliminary work, we have identified MEKK2, a kinase member of the MAPK signaling cascade, as a SMYD3 substrate. I will employ biochemical, molecular, cellular, and genetic approaches to assess the physiological and pathological functions of SMYD3 in cancer cells, including its potential effect of MEKK2 activity in cells. These studies will reveal new key molecular pathways that regulate cancer cell behavior and may identify novel targeted therapeutic strategies for the treatment of cancer.
 
 The successful completion of the proposed aims will advance the field of cancer biology and the field of signal transduction. Determining the importance of SMYD3 early expression in lung cancer protein and its enzymatic function in cancer cells is a novel way to identify novel approaches to detect and treat lung cancer. Additionally I believe that my studies will reveal key new molecular pathways that regulate cancer cell behavior and may identify novel targeted therapeutic strategies for treatment of cancer.