2. Academic Validation
  3. METTL3-mediated N6-methyladenosine modification and HDAC5/YY1 promote IFFO1 downregulation in tumor development and chemo-resistance

METTL3-mediated N6-methyladenosine modification and HDAC5/YY1 promote IFFO1 downregulation in tumor development and chemo-resistance

  • Cancer Lett. 2022 Oct 15;215971. doi: 10.1016/j.canlet.2022.215971.
Ye Zhang 1,  Jian-Ge Qiu 1,  Xiao-Yu Jia 1,  Yu Ke 2,  Ming-Kun Zhang 2,  David Stieg 3,  Wen-Jing Liu 4,  Ling-Zhi Liu 3,  Lin Wang 5,  Bing-Hua Jiang 6
Affiliations

Affiliations

  • 1 Academy of Medical Science, School of Basic Medical Science, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, 450008, China.
  • 2 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 3 Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 4 Academy of Medical Science, School of Basic Medical Science, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, 450008, China; Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 5 Academy of Medical Science, School of Basic Medical Science, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, 450008, China. Electronic address: wanglinzz@zzu.edu.cn.
  • 6 Academy of Medical Science, School of Basic Medical Science, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, 450008, China; Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Electronic address: binghjiang@zzu.edu.cn.
PMID: 36257380 DOI: 10.1016/j.canlet.2022.215971
Abstract

Ovarian Cancer (OC) is a malignant tumor that seriously threatens women's health. Due to the difficulty of early diagnosis, most patients exhibit advanced disease or peritoneal metastasis at diagnosis. We discovered that IFFO1 is a novel tumor suppressor, but its role in tumorigenesis, development and chemoresistance is unknown. In this study, IFFO1 levels were downregulated across cancers, leading to the acceleration of tumor development, metastasis and/or cisplatin resistance. Overexpression of IFFO1 inhibited the translocation of β-catenin to the nucleus and decreased tumor metastasis and cisplatin resistance. Furthermore, we demonstrated that IFFO1 was regulated at both the transcriptional and posttranscriptional levels. At the transcriptional level, the recruitment of HDAC5 inhibited IFFO1 expression, which is mediated by the transcription factor YY1, and the METTL3/YTHDF2 axis regulated the mRNA stability of IFFO1 in an m6A-dependent manner. Mice injected with IFFO1-overexpressing cells had lower ascites volumes and tumor weights throughout the peritoneal cavity than those injected with parental cells expressing the vector control. In conclusion, we demonstrated that IFFO1 is a novel tumor suppressor that inhibits tumor metastasis and reverses drug resistance in ovarian Cancer. IFFO1 was downregulated at both the transcriptional level and posttranscriptional level by histone deacetylase and RNA methylation, respectively, and the IFFO1 signaling pathway was identified as a potential therapeutic target for Cancer.

Keywords

Chemoresistance; HDAC5; IFFO1; METTL3; Tumor metastasis.

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