Enhancer hijacking drives FAM20C expression to promote papillary thyroid cancer progression

Papillary thyroid cancer (PTC) is the most common endocrine cancer, with a good prognosis in most cases. However, aggressive PTC can metastasise or reoccur and become refractory disease. Therefore, it's urgent to uncover new biomarkers for aggressive PTC. Accumulating evidence suggests that aberrant enhancers and targeted gene transcription drive the progression of PTC. To identify the cancer-specific enhancers and their downstream genes in PTC, we profiled the transcriptomes (RNA-seq) and enhancer-based epigenomic reorganisation (ChIP-seq) of cancer tissues and matched normal tissues from three PTC patients. Importantly, six candidate genes (RHBDF1, FAM20C, PHLDA2, TMPRSS6, LAD1, and BGN) were identified to be consistently upregulated by enhancers in PTC and correlated with prognosis. Further experiments verified the function of enhancers governing FAM20C in regulating PTC tumorigenesis, thereby unveiling a FAM20C-governed oncogenic mechanism for suppressing two cytokines (TNF-α and TGF-β) in PTC. Additionally, we demonstrated that a FAM20C inhibitor (3r) suppressed the proliferation and invasion of thyroid cancer cells in vitro and vivo. Moreover, FAM20C is driven by KLF12 through its enhancer. Collectively, our study uncovers the potential correlations between the aberrant activation of cancer-specific enhancers and PTC tumorigenesis and identifies FAM20C as a novel target for PTC.