Estrogen-related receptor alpha promotes thyroid tumor cell survival via a tumor subtype-specific regulation of target gene networks. Oncogene 2024 Jul;43(31):2431-2446
Date
06/28/2024Pubmed ID
38937602DOI
10.1038/s41388-024-03078-1Scopus ID
2-s2.0-85197858420 (requires institutional sign-in at Scopus site)Abstract
Mortalin (encoded by HSPA9) is a mitochondrial chaperone often overexpressed in cancer through as-yet-unknown mechanisms. By searching different RNA-sequencing datasets, we found that ESRRA is a transcription factor highly correlated with HSPA9 in thyroid cancer, especially in follicular, but not C cell-originated, tumors. Consistent with this correlation, ESRRA depletion decreased mortalin expression only in follicular thyroid tumor cells. Further, ESRRA expression and activity were relatively high in thyroid tumors with oncocytic characteristics, wherein ESRRA and mortalin exhibited relatively high functional overlap. Mechanistically, ESRRA directly regulated HSPA9 transcription through a novel ESRRA-responsive element located upstream of the HSPA9 promoter. Physiologically, ESRRA depletion suppressed thyroid tumor cell survival via caspase-dependent apoptosis, which ectopic mortalin expression substantially abrogated. ESRRA depletion also effectively suppressed tumor growth and mortalin expression in the xenografts of oncocytic or ESRRA-overexpressing human thyroid tumor cells in mice. Notably, our Bioinformatics analyses of patient data revealed two ESRRA target gene clusters that contrast oncocytic-like and anaplastic features of follicular thyroid tumors. These findings suggest that ESRRA is a tumor-specific regulator of mortalin expression, the ESRRA-mortalin axis has higher significance in tumors with oncocytic characteristics, and ESRRA target gene networks can refine molecular classification of thyroid cancer.
Author List
Chen W, Song YS, Lee HS, Lin CW, Lee J, Kang YE, Kim SK, Kim SY, Park YJ, Park JIAuthors
Chien-Wei Lin PhD Associate Professor in the Data Science Institute department at Medical College of WisconsinJong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cell Line, Tumor
Cell Survival
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
HSP70 Heat-Shock Proteins
Humans
Mice
Mitochondrial Proteins
Promoter Regions, Genetic
Receptors, Estrogen
Thyroid Neoplasms
