Theranostics 2022; 12(4):1500-1517. doi:10.7150/thno.66142 This issue

Research Paper

KDM1A promotes thyroid cancer progression and maintains stemness through the Wnt/β-catenin signaling pathway

Wei Zhang1,2,3#, Xianhui Ruan1#, Yaoshuang Li4, Jingtai Zhi5, Linfei Hu1, Xiukun Hou1, Xianle Shi6, Xin Wang1, Jinpeng Wang7, Weike Ma1, Pengfei Gu1, Xiangqian Zheng1✉, Ming Gao1,2✉

1. Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
2. Department of Breast and Thyroid Surgery, Tianjin Union Medical Center, No.190 Jieyuan Road, Hongqiao District, Tianjin 300121, P R China
3. School of Medicine, Nankai University, Tianjin 300071, China
4. Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, 190 of Jieyuan Road, Hongqiao District, Tianjin, 300121, China
5. Department of Otolaryngology-Head and Neck Surgery, Tianjin First Center Hospital, Nankai District of Tianjin, Institute of Otolaryngology of Tianjin, Key Laboratory of Auditory Speech and Balance Medicine, Key Clinical Discipline of Tianjin (Otolaryngology), Otolaryngology Clinical Quality Control Centre, Rehabilitation Road No. 24, Tianjin, 300192, China
6. Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY 10032, USA
7. Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, 300060, Tianjin, China
#These authors contributed equally to this work.

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Citation:
Zhang W, Ruan X, Li Y, Zhi J, Hu L, Hou X, Shi X, Wang X, Wang J, Ma W, Gu P, Zheng X, Gao M. KDM1A promotes thyroid cancer progression and maintains stemness through the Wnt/β-catenin signaling pathway. Theranostics 2022; 12(4):1500-1517. doi:10.7150/thno.66142. Available from https://www.thno.org/v12p1500.htm

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Abstract

Graphic abstract

Background: Cancer stem cells (CSCs) are highly tumorigenic, chemotherapy-resistant, tumor growth-sustaining, and are implicated in tumor recurrence. Previous studies have shown that lysine-specific histone demethylase 1A (KDM1A) is highly expressed in several human malignancies and CSCs. However, the role of KDM1A in CSCs and the therapeutic potential of KDM1A inhibitors for the treatment of the advanced thyroid cancer are poorly understood.

Methods: Firstly, KDM1A was identified as an important epigenetic modifier that maintained the stemness of thyroid cancer through a mini histone methylation modifier screen and confirmed in thyroid cancer tissues and cell lines. RNA sequence was performed to discover the downstream genes of KDM1A. The underlying mechanisms were further investigated by ChIP, IP and dual luciferase reporter assays, gain and loss of function assays.

Results: Here we report that KDM1A regulates the stemness of thyroid cancer and promotes thyroid cancer progression via the Wnt/β-catenin pathway. Mechanistically, KDM1A down-regulates two antagonists of the canonical Wnt pathway, APC2 and DKK1, by demethylating H3K4me1/2 of the APC2 promoter region and the nonhistone substrate HIF-1α, resulting in the inhibition of APC2 transcription and the activation of the HIF-1α/microRNA-146a/DKK1 axis. Importantly, we also demonstrate that GSK-LSD1, a highly selective inhibitor of KDM1A, significantly inhibits thyroid cancer progression and enhances the sensitivity of thyroid cancer to chemotherapy.

Conclusions: KDM1A plays an important role in thyroid cancer progression and maintains stemness, our study provides a new strategy for the therapy of advanced thyroid cancer.

Keywords: KDMIA, thyroid cancer, Wnt/β-catenin pathway, stemness, target therapy