TY - JOUR
T1 - The Epithelial Sodium Channel (αENaC) Is a Downstream Therapeutic Target of ASCL1 in Pulmonary Neuroendocrine Tumors
AU - He, Min
AU - Liu, Shanshan
AU - Gallolu Kankanamalage, Sachith
AU - Borromeo, Mark D.
AU - Girard, Luc
AU - Gazdar, Adi F.
AU - Minna, John D.
AU - Johnson, Jane E.
AU - Cobb, Melanie H.
N1 - Funding Information:
This work was supported by grants from the Cancer Prevention and Research Institute of Texas jointly to M. H. C. and J. E. J. (RP140143) and by National Institutes of Health (R37 DK34128 to M.H.C. and P50CA70907 to J.D.M.), grants from the DOD PROSPECT and Longenbaugh Foundation to J. D. M., and the Robert A. Welch Foundation to M. H. C. (I1243). The final experiments were also supported by NCI U01 CA213338-01A1 to Minna, Johnson, Gazdar, and Cobb. The authors gratefully acknowledge assistance from the Harold C. Simmons Comprehensive Cancer Center core facilities supported in part by the National Cancer Institute (P30CA142543).
Funding Information:
This work was supported by grants from the Cancer Prevention and Research Institute of Texas jointly to M. H. C. and J. E. J. ( RP140143 ) and by National Institutes of Health ( R37 DK34128 to M.H.C. and P50CA70907 to J.D.M.), grants from the DOD PROSPECT and Longenbaugh Foundation to J. D. M., and the Robert A. Welch Foundation to M. H. C. ( I1243 ). The final experiments were also supported by NCI U01 CA213338-01A1 to Minna, Johnson, Gazdar, and Cobb. The authors gratefully acknowledge assistance from the Harold C. Simmons Comprehensive Cancer Center core facilities supported in part by the National Cancer Institute ( P30CA142543 ).
Publisher Copyright:
© 2018
PY - 2018/4
Y1 - 2018/4
N2 - Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcitrant cancer by the National Cancer Institute, in urgent need of new rational therapeutic targets. Previous studies have determined that the basic helix-loop-helix transcription factor achaete-scute homolog 1 (ASCL1) is essential for the survival and progression of a fraction of pulmonary neuroendocrine cancer cells, which include both SCLC and a subset of non-SCLC. Previously, to understand how ASCL1 initiates tumorigenesis in pulmonary neuroendocrine cancer and identify the transcriptional targets of ASCL1, whole-genome RNA-sequencing analysis combined with chromatin immunoprecipitation-sequencing was performed with a series of lung cancer cell lines. From this analysis, we discovered that the gene SCNN1A, which encodes the alpha subunit of the epithelial sodium channel (αENaC), is highly correlated with ASCL1 expression in SCLC. The product of the SCNN1A gene ENaC can be pharmacologically inhibited with amiloride, a drug that has been used clinically for close to 50 years. Amiloride inhibited growth of ASCL1-dependent SCLC more strongly than ASCL1-independent SCLC in vitro and slowed growth of ASCL1-driven SCLC in xenografts. We conclude that SCNN1A/αENaC is a direct transcriptional target of the neuroendocrine lung cancer lineage oncogene ASCL1 that can be pharmacologically targeted with antitumor effects.
AB - Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcitrant cancer by the National Cancer Institute, in urgent need of new rational therapeutic targets. Previous studies have determined that the basic helix-loop-helix transcription factor achaete-scute homolog 1 (ASCL1) is essential for the survival and progression of a fraction of pulmonary neuroendocrine cancer cells, which include both SCLC and a subset of non-SCLC. Previously, to understand how ASCL1 initiates tumorigenesis in pulmonary neuroendocrine cancer and identify the transcriptional targets of ASCL1, whole-genome RNA-sequencing analysis combined with chromatin immunoprecipitation-sequencing was performed with a series of lung cancer cell lines. From this analysis, we discovered that the gene SCNN1A, which encodes the alpha subunit of the epithelial sodium channel (αENaC), is highly correlated with ASCL1 expression in SCLC. The product of the SCNN1A gene ENaC can be pharmacologically inhibited with amiloride, a drug that has been used clinically for close to 50 years. Amiloride inhibited growth of ASCL1-dependent SCLC more strongly than ASCL1-independent SCLC in vitro and slowed growth of ASCL1-driven SCLC in xenografts. We conclude that SCNN1A/αENaC is a direct transcriptional target of the neuroendocrine lung cancer lineage oncogene ASCL1 that can be pharmacologically targeted with antitumor effects.
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U2 - 10.1016/j.tranon.2018.01.004
DO - 10.1016/j.tranon.2018.01.004
M3 - Article
C2 - 29413762
AN - SCOPUS:85044764269
SN - 1936-5233
VL - 11
SP - 292
EP - 299
JO - Translational Oncology
JF - Translational Oncology
IS - 2
ER -