Theranostics 2021; 11(9):4298-4315. doi:10.7150/thno.51342

Research Paper

N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization

Chen Chen1,2,5, Weitang Yuan1, Quanbo Zhou1, Bo Shao1,5, Yuying Guo1,5, Weiwei Wang6, Shuaixi Yang1,5, Yaxin Guo3,4,5, Luyang Zhao3,4,5, Qin Dang1,5, Xiuxiu Yang1,5, Guixian Wang1, Qiaozhen Kang2, Zhenyu Ji3,4✉, Jinbo Liu1✉, Zhenqiang Sun1,5✉

1. Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
2. School of Life Science, Zhengzhou University, Zhengzhou, 450001, Henan, China.
3. Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China.
4. School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450002, Henan, China.
5. Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China.
6. Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, Henan, China.

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Citation:
Chen C, Yuan W, Zhou Q, Shao B, Guo Y, Wang W, Yang S, Guo Y, Zhao L, Dang Q, Yang X, Wang G, Kang Q, Ji Z, Liu J, Sun Z. N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization. Theranostics 2021; 11(9):4298-4315. doi:10.7150/thno.51342. Available from https://www.thno.org/v11p4298.htm

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Abstract

Tumor metastasis is the leading cause of death in patients with colorectal cancer (CRC). Circular RNAs (circRNAs) have been shown to be involved in cancer progression. However, the regulatory mechanisms of circRNAs involved in CRC tumor metastasis are currently unknown.

Methods: High-throughput sequencing was performed on 6 pairs of CRC and adjacent normal tissues to identify the expression profiles of mRNA and circRNA. circ1662 was assessed by RNA-ISH and IHC of a tissue chip. The function of circ1662 in CRC was evaluated by knocking down or overexpressing circ1662. MeRIP-qPCR, RIP-qPCR, and RNA pull-down were performed to determine the relationship between METTL3, circ1662, and YAP1.

Results: A novel circRNA, circ1662, exhibited significantly higher expression in CRC tissues than paired normal tissues. High circ1662 expression was correlated with poor prognosis and tumor depth in patients with CRC. Functionally, circ1662 promoted CRC cell invasion and migration by controlling EMT in vitro and in vivo. Mechanistically, circ1662 directly bound to YAP1 and accelerated its nuclear accumulation to regulate the SMAD3 pathway. Additionally, circ1662 enhanced CRC invasion and migration depending on YAP1 and SMAD3. Interestingly, METTL3 induced circ1662 expression by binding its flanking sequences and installing m6A modifications. Clinically, circ1662 expression strongly correlated with METTL3 and YAP1 protein expression. Moreover, YAP1 expression was negatively correlated with SMAD3 expression.

Conclusions: METTL3-induced circ1662 promoted CRC cell invasion and migration by accelerating YAP1 nuclear transport. This result implies that circ1662 is a new prognostic and therapeutic marker for CRC metastasis.

Keywords: colorectal cancer, N6-methyladenosine (m6A), METTL3, circ1662, YAP1