Language
English
Publication Date
3-1-2023
Journal
Journal of Clinical Investigation
DOI
10.1172/JCI159940
PMID
36856111
PMCID
PMC9974104
PubMedCentral® Posted Date
3-1-2023
PubMedCentral® Full Text Version
Post-print
Abstract
Emerging evidence suggests that cryptic translation within long noncoding RNAs (lncRNAs) may produce novel proteins with important developmental/physiological functions. However, the role of this cryptic translation in complex diseases (e.g., cancer) remains elusive. Here, we applied an integrative strategy combining ribosome profiling and CRISPR/Cas9 screening with large-scale analysis of molecular/clinical data for breast cancer (BC) and identified estrogen receptor α-positive (ER+) BC dependency on the cryptic ORFs encoded by lncRNA genes that were upregulated in luminal tumors. We confirmed the in vivo tumor-promoting function of an unannotated protein, GATA3-interacting cryptic protein (GT3-INCP) encoded by LINC00992, the expression of which was associated with poor prognosis in luminal tumors. GTE-INCP was upregulated by estrogen/ER and regulated estrogen-dependent cell growth. Mechanistically, GT3-INCP interacted with GATA3, a master transcription factor key to mammary gland development/BC cell proliferation, and coregulated a gene expression program that involved many BC susceptibility/risk genes and impacted estrogen response/cell proliferation. GT3-INCP/GATA3 bound to common cis regulatory elements and upregulated the expression of the tumor-promoting and estrogen-regulated BC susceptibility/risk genes MYB and PDZK1. Our study indicates that cryptic lncRNA-encoded proteins can be an important integrated component of the master transcriptional regulatory network driving aberrant transcription in cancer, and suggests that the "hidden" lncRNA-encoded proteome might be a new space for therapeutic target discovery.
Keywords
Humans, Female, RNA, Long Noncoding, Open Reading Frames, CRISPR-Cas Systems, Breast Neoplasms, Estrogens, Breast cancer, Noncoding RNAs, Translation, Genetics, Oncology
Published Open-Access
yes
Recommended Citation
Zheng, Caishang; Wei, Yanjun; Zhang, Peng; et al., "CRISPR/Cas9 Screen Uncovers Functional Translation of Cryptic lncRNA-Encoded Open Reading Frames in Human Cancer" (2023). Faculty and Staff Publications. 258.
https://digitalcommons.library.tmc.edu/baylor_docs/258
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Genetic Phenomena Commons, Genetic Processes Commons, Medical Genetics Commons, Obstetrics and Gynecology Commons, Oncology Commons