Novel role of ASH1L histone methyltransferase in anaplastic thyroid carcinoma

Abstract

<jats:p>Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with an average life expectancy of ∼6 months from the time of diagnosis. The genetic and epigenetic changes that underlie this malignancy are incompletely understood. We found that ASH1-like histone lysine methyltransferase (ASH1L) is overexpressed in ATC relative to the much less aggressive and more common differentiated thyroid cancer. This increased expression was due at least in part to reduced levels of microRNA-200b-3p (miR-200b-3p), which represses ASH1L expression, in ATC. Genetic knockout of ASH1L protein expression in ATC cell lines decreased cell growth both in culture and in mouse xenografts. RNA-Seq analysis of ASH1L knockout <jats:italic>versus</jats:italic> WT ATC cell lines revealed that ASH1L is involved in the regulation of numerous cancer-related genes and gene sets. The pro-oncogenic long noncoding RNA colon cancer-associated transcript 1 (CCAT1) was one of the most highly (approximately 68-fold) down-regulated transcripts in ASH1L knockout cells. Therefore, we investigated CCAT1 as a potential mediator of the growth-inducing activity of ASH1L. Supporting this hypothesis, CCAT1 knockdown in ATC cells decreased their growth rate, and ChIP-Seq data indicated that CCAT1 is likely a direct target of ASH1L's histone methyltransferase activity. These results indicate that ASH1L contributes to the aggressiveness of ATC and suggest that ASH1L, along with its upstream regulator miR-200b-3p and its downstream mediator CCAT1, represents a potential therapeutic target in ATC.</jats:p>

TERT Promoter Mutated Follicular Thyroid Carcinomas Exhibit a Distinct microRNA Expressional Profile with Potential Implications for Tumor Progression

“…However, the results obtained from this study are based on a small sample series in need of experimental validation. For example, our findings of overexpressed hsa-miR-200b-3p in TERT promoter mutated FTCs are in conflict with the previously demonstrated down-regulation in ATCs, thereby serving as a good example for a miRNA candidate reliant on further analyses using larger tumor cohorts as well as the inclusion of normal controls [9].…”

Long non-coding RNA signatures as predictors of prognosis in thyroid cancer: a narrative review

“…It is located at chromosome 8q24.21, and is in the vicinity of the proto-oncogene c-MYC (51). CCTA1 has (52). These prior experimental data strongly suggest that CCTA1 exhibits oncogenic behavior in TC.…”

Poorly Differentiated and Anaplastic Thyroid Cancer: Insights into Genomics, Microenvironment and New Drugs

“…lncRNA are RNAs longer than 200 nucleotides that do not encode proteins but regulate gene expression, splicing and nucleation of subnuclear domains [49]; moreover, lncRNAs may have cytoplasmic functions, such as miRNA sponging, interaction with signaling proteins, and further modulation of mRNA translation [49]. In ATC, lncRNAs may regulate tumor growth [84,85], invasiveness [86], and both tumor growth and invasiveness [87][88][89][90][91]; they can also regulate cancer sensitivity to treatments [92]. In particular, lncRNA PTCSC3 was described at low levels both in ATC tissue and cell lines and it was demonstrated that its upregulation inhibited the resistance to doxorubicin by suppressing stem cell proprieties [92].…”