The role of T2E mediated CBF-1/RBP-Jκ signaling in metastatic thyroid cancer.

Hu, An; Cao, Fan-Fan; Lu, Dan; Yang, Li-Yun

OBJECTIVE Cancer has been shown to be an independent risk factor for 2019-nCoV. Expression of transmembrane serine protease 2 (TMPRSS2) is abnormal in many cancers. Nevertheless, system analysis of TMPRSS2-ERG (T2E) abnormalities in metastatic thyroid cancer remains to be elucidated. METHOD Using genomic and chromatin data, we demonstrate a unique cis-regulatory landscape between non-T2E and T2E-positive metastatic thyroid cancers, including clusters of regulatory elements (COREs). We attempt to describe the effect of T2E silencing on the cis-regulatory structure in metastatic thyroid cancers and its phase with the obvious phenotype characteristics of T2E-positive metastatic thyroid cancers. RESULTS These differences were linked by the ERG (erythroblast transformation-specific related gene) co-opts of FoxA1 and HOXB13, which realized T2E specific transcription profile. The study also demonstrated the T2E-specific CORE in an ERG site of structural rearrangement, which is due to the expansion of the T2E locus and contributes to its up-expression. Ultimately, we demonstrate that T2E-specific transcription profile is the basis of vulnerability of CBF-1/RBP-Jκ pathway. In fact, CBF-1/RBP-Jκ pathway inhibits the invasion and growth of T2E-positive thyroid tumors. CONCLUSION This study indicates that the overexpression of ERG co-option has a unique cis-regulatory structure in T2E positive thyroid tumors, which induces drug dependence on CBF-1/RBP-Jκ signal. Our study solved the genetic and epigenetic variation of T2E in metastatic thyroid cancer for the first time. It is worth noting that further functional and clinical validation is needed as our study is a bioinformatics analysis.