Epigenetic inhibition of CTCF by HN1 promotes dedifferentiation and stemness of anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is one of the deadliest cancers, whose important malignant feature is dedifferentiation. Chromatin remodeling is critical for tumorigenesis and progression, while its roles and regulator in facilitating dedifferentiation of ATC had been poorly understood. In our study, an emerging function of hematological and neurological expressed 1 (HN1) in promoting dedifferentiation of ATC cells was uncovered. HN1 expression was negatively correlated with the thyroid differentiation markers both at mRNA and protein level. Knockdown of HN1 in ATC cells effectively upregulated the thyroid differentiation markers and impeded the sphere formation capacity, accompanying with the loss of cancer stemness. In contrast, overexpression of HN1 drove the gain of stemness and the loss of thyroid differentiation markers. Nude mouse and zebrafish xenograft models showed that inhibition of HN1 in ATC cells effectively hindered tumor growth due to the loss of cancer stemness. Further study showed that HN1 was negatively correlated with CTCF in an independent thyroid-cancer cohort, and inhibition of HN1 enhanced the expression of CTCF in ATC cells. Overexpression of CTCF significantly reversed the dedifferentiation phenotypes of ATC cells, whereas simultaneously inhibiting HN1 and CTCF was unable to recover the level of thyroid differentiation markers. The combination of ATAC-seq and ChIP-seq analysis confirmed that CTCF regulated genes relating with thyroid gland development through influencing their chromatin accessibility. HN1 inhibited the acetylation of H3K27 at the promoter of CTCF by recruiting HDAC2, thereby inhibiting the transcriptional activation of CTCF. These findings demonstrated an essential role of HN1 in regulating the chromatin accessibility of thyroid differentiation genes during ATC dedifferentiation.

Automated summary

This study uncovered the emerging role of HN1 in promoting dedifferentiation of anaplastic thyroid cancer (ATC) cells. HN1 negatively regulated the thyroid differentiation markers and had an inhibitory effect on the transcriptional activation of CTCF, thereby influencing the chromatin accessibility of thyroid differentiation genes.