Lysine-Specific Demethylase 1 Affects the Progression of Papillary Thyroid Carcinoma via HIF1α and microRNA-146a

Abstract

Context: Lysine-specific demethylase 1 (LSD1) stabilizes hypoxia-inducible factor 1α (HIF1α) to advance tumor progression, while HIF1α functions as a transcription factor to increase the expression of microRNA-146a (miR-146a).

Objective: We aim to investigate whether LSD1 affects the development of papillary thyroid carcinoma (PTC) via HIF1α and miR-146a.

Design: In vitro assays were performed with Nthy-ori 3-1, BHP5-16, BCPAP, K1, and BHP2-7 cell lines. In vivo assays were conducted with established xenograft tumors in nude mice.

Setting: This study was conducted at our lab.

Patients and materials: PTC tissues and corresponding adjacent normal tissues were obtained from 45 patients hospitalized in Sun Yat-Sen Memorial Hospital. Assays were conducted using Nthy-ori 3-1, BHP5-16, BCPAP, K1, and BHP2-7 cell lines, as well as 50 male BALB/c nude mice.

Intervention: Cells were transfected with sh-LSD1, sh-GABPA, oe-LSD1, oe-HIF1α, miR-146a mimic, and miR-146a inhibitor. In addition, K1 cells expressing lv-oe-LSD1, lv-miR-146a inhibitor, lv-oe-LSD1 or miR-146a inhibitor were injected into the right side of the mice. LSD1 gene and protein expression patterns were analyzed in 45 clinical PTC tissue samples.

Main outcome measure: Expression of LSD1, HIF1α, miR-146a, and GA-binding protein transcription factor alpha (GABPA), as well as their effects on PTC.

Results: LSD1 was highly expressed in clinical PTC tissues. LSD1 stabilized HIF1α and inhibited the degradation of its ubiquitin proteasome. HIF1α was enriched in the promoter region of miR-146a, an upregulated miRNA in PTC. HIF1α increased miR-146a expression to promote PTC progression in vitro, which was achieved by inhibiting GABPA, a target gene of miR-146a. LSD1 upregulated miR-146a to enhance the development and metastasis of PTC in nude mice.

Conclusion: Our results show that LSD1 functions as an oncogene in PTC by upregulating HIF1α and miR-146a, elucidating an understanding of undefined mechanisms associated with tumor progression in PTC.

Keywords: GA binding protein transcription factor alpha; hypoxia-inducible factor 1α; lysine-specific demethylase 1; microRNA-146a; papillary thyroid carcinoma; transcription factor.