DNA-PKcs as an upstream mediator of OCT4-induced MYC activation in small cell lung cancer

Small cell lung cancer (SCLC) is a neuroendocrine tumor noted for the rapid development of both metastases and resistance to chemotherapy. High mutation burden, ubiquitous loss of TP53 and RB1, and a mutually exclusive amplification of MYC gene family members contribute to genomic instability and ma...

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Published in:Biochimica et biophysica acta. Gene regulatory mechanisms 2023-06, Vol.1866 (2), p.194939-194939, Article 194939
Main Authors: Wei, Sung-Jen, Yang, In-Hyoung, Mohiuddin, Ismail S., Kshirsagar, Ganesh J., Nguyen, Thinh H., Trasti, Scott, Maurer, Barry J., Kang, Min H.
Format: Article
Language:English
Subjects:
c-MYC
DNA
DNA-PKcs
Humans
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Narciclasine
Neuroendocrine Tumors
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Small cell lung cancer
Small Cell Lung Carcinoma - genetics
Transcriptional activation
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Summary:Small cell lung cancer (SCLC) is a neuroendocrine tumor noted for the rapid development of both metastases and resistance to chemotherapy. High mutation burden, ubiquitous loss of TP53 and RB1, and a mutually exclusive amplification of MYC gene family members contribute to genomic instability and make the development of new targeted agents a challenge. Previously, we reported a novel OCT4-induced MYC transcriptional activation pathway involving c-MYC, pOCT4S111, and MAPKAPK2 in progressive neuroblastoma, also a neuroendocrine tumor. Using tumor microarray analysis of clinical samples and preclinical models, we now report a correlation in expression between these proteins in SCLC. In correlating c-MYC protein expression with genomic amplification, we determined that some SCLC cell lines exhibited high c-MYC without genomic amplification, implying amplification-independent MYC activation. We then confirmed direct interaction between OCT4 and DNA-PKcs and identified specific OCT4 and DNA-PKcs binding sites. Knock-down of both POU5F1 (encoding OCT4) and PRKDC (encoding DNA-PKcs) resulted in decreased c-MYC expression. Further, we confirmed binding of OCT4 to the promoter/enhancer region of MYC. Together, these data establish the presence of a DNA-PKcs/OCT4/c-MYC pathway in SCLCs. We then disruptively targeted this pathway and demonstrated anticancer activity in SCLC cell lines and xenografts using both DNA-PKcs inhibitors and a protein-protein interaction inhibitor of DNA-PKcs and OCT4. In conclusion, we demonstrate here that DNA-PKcs can mediate high c-MYC expression in SCLCs, and that this pathway may represent a new therapeutic target for SCLCs with high c-MYC expression. •MYC transcriptional activation independent of genomic amplification by OCT4 via a kinase DNA-PKcs in small cell lung cancer.•The first-in-class agent targeting MYC by inhibiting a key kinase interaction with OCT4 that regulates c-MYC expression.•Identifying the upsteam molecules of c-MYC, undruggable target, to regulate the expression of c-MYC in small cell lung cancer.
ISSN:1874-9399
1876-4320
DOI:10.1016/j.bbagrm.2023.194939