2. Academic Validation
  3. M6A modification mediates CACNA1A stability to drive the progression of ovarian cancer by inhibiting ferroptosis

M6A modification mediates CACNA1A stability to drive the progression of ovarian cancer by inhibiting ferroptosis

  • J Ovarian Res. 2025 Nov 29;19(1):4. doi: 10.1186/s13048-025-01907-9.
Xieyang Gong # 1 2,  Jingmeng Wang # 3,  Anlong Jiang 4,  Changxin Shao 3,  Yuan Jiang 5,  Ye Kuang 3,  Yimei Meng 3,  Mingjiao Ma 3,  Zihe Qin 6,  Yizhen Chen 6,  Yutong Fan 7,  Huike Yang 8 9,  Peiling Li 10
Affiliations

Affiliations

  • 1 Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 2 Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang Province, Harbin, China.
  • 3 Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, No 246, Xuefu Road, Nangang District, Harbin, Heilongjiang, 150001, China.
  • 4 Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 5 Department of Pharmacy, Harbin Medical University, Harbin, China.
  • 6 Department of Anatomy, School of Basic Medical Sciences, Harbin Medical University, No157, Baojian Road, Nangang District, , Harbin, China.
  • 7 Harbin Medical University, Harbin, China.
  • 8 Department of Anatomy, School of Basic Medical Sciences, Harbin Medical University, No157, Baojian Road, Nangang District, , Harbin, China. [email protected].
  • 9 Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China, Harbin Medical University, Ministry of Education, Harbin, China. [email protected].
  • 10 Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, No 246, Xuefu Road, Nangang District, Harbin, Heilongjiang, 150001, China. [email protected].
  • # Contributed equally.
PMID: 41316396 DOI: 10.1186/s13048-025-01907-9
Abstract

Ovarian Cancer is a particularly lethal form of Cancer affecting the female reproductive system. Prior research indicates a strong link between RNA epigenetic modification and the development of Cancer. How different RNA modifications interact and affect Cancer biological processes is not yet clearly understood. Our research using ovarian Cancer tissue microarrays reveals that IGF2BP3, as crucial 'reader' of m6A, is considerably upregulated and correlated with negative clinical results. In vitro experiments IGF2BP3 stimulates the multiplication of ovarian Cancer cells while inhibiting Ferroptosis. Meanwhile, we identified firstly CACNA1A mediated by m6A modification as an innovative direct target of IGF2BP3 through RNA-Seq and MeRIP-seq and the m6A-modified CACNA1A was a crucial modulator to regulate the cellular process of ovarian Cancer. Subsequently, calcium-dependent Ferroptosis was assessed as an underlying mechanism of CACNA1A in ovarian Cancer using transmission electron microscopy and flow cytometry, where CACNA1A knockdown led to abnormal calcium uptake and intracellular calcium overload, resulting in excessive Reactive Oxygen Species (ROS) accumulation and subsequent Ferroptosis induction. Furthermore, we identified in first that the elevated levels of IGF2BP3 were a result of its super enhancer and key transcription factor TFAP2A enrichment in IGF2BP3 gene. Overall, this study elucidates that super enhancer-driven IGF2BP3 targets CACNA1A via m6A modification, in turn which inhibits Ferroptosis in ovarian Cancer. It highlights that targeting the IGF2BP3-CACNA1A regulatory axis could be an effective strategy impeding ovarian Cancer progression.

Keywords

M6A modification; CACNA1A; Ferroptosis; IGF2BP3; Ovarian cancer.

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