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  3. The mTORC2 subunit RICTOR drives breast cancer progression by promoting ganglioside biosynthesis through transcriptional and epigenetic mechanisms

The mTORC2 subunit RICTOR drives breast cancer progression by promoting ganglioside biosynthesis through transcriptional and epigenetic mechanisms

  • PLoS Biol. 2025 Sep 11;23(9):e3003362. doi: 10.1371/journal.pbio.3003362.
Mohammad Nafees Ansari 1 2,  Somesh K Jha 3,  Ali Khan 1,  Kajal Rajput 1,  Nishant Pandey 3,  Dolly Jain 3,  Rajeshwari Tripathi 4,  Nihal Medatwal 3,  Pankaj Sharma 1,  Sudeshna Datta 2,  Animesh Kar 3,  Trishna Pani 1,  Sk Asif Ali 2,  Kaushavi Cholke 1,  Kajal Rana 3,  Valiya P Snijesh 5 6,  Geetashree Mukherjee 7,  Suryanarayana V S Deo 8,  Soumen Basak 2,  Ashutosh Mishra 8,  Jyothi S Prabhu 5,  Arnab Mukhopadhyay 2,  Avinash Bajaj 3,  Ujjaini Dasgupta 1 4
Affiliations

Affiliations

  • 1 Amity Institute of Integrative Sciences and Health, Amity University Haryana, Gurgaon, Haryana, India.
  • 2 National Institute of Immunology, New Delhi, India.
  • 3 Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India.
  • 4 Koita Centre for Digital Health-Ashoka, Trivedi School of Biosciences, Ashoka University, Sonipat, India.
  • 5 Division of Molecular Medicine, St. Johns Research Institute, St Johns National Academy of Health Sciences, Bangalore, Karnataka, India.
  • 6 Centre for Doctoral Studies, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India.
  • 7 Tata Medical Center, Kolkata, West Bengal, India.
  • 8 Department of Surgical Oncology, BRA-Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
PMID: 40934285 DOI: 10.1371/journal.pbio.3003362
Abstract

Sphingolipid and ganglioside metabolic pathways are crucial components of cell signaling, having established roles in Cancer cell proliferation, invasion, and migration. However, regulatory mechanisms controlling sphingolipid and ganglioside biosynthesis in mammalian cells are less known. Here, we show that RICTOR, the regulatory subunit of mTORC2, regulates the synthesis of sphingolipids and gangliosides in human luminal breast cancer-specific MCF-7 and BT-474 cells through transcriptional and epigenetic mechanisms. We observe that RICTOR regulates glucosylceramide levels by modulating the expression of UDP-Glucose Ceramide Glucosyl transferase (UGCG). We identify Zinc Finger Protein X-linked (ZFX) as a RICTOR-responsive transcription factor whose recruitment to the UGCG promoter is regulated by DNA Methyltransferase 1 and Histone Demethylase (KDM5A), which are known Akt substrates. We further demonstrate that RICTOR regulates the synthesis of GD3 gangliosides through ZFX and UGCG, and triggers the activation of the EGFR signaling pathway, thereby promoting tumor growth. In line with our findings in human Cell Culture and mouse models, we observe an elevated expression of RICTOR, ZFX, and UGCG in Indian luminal breast Cancer tissues and in TCGA and METABRIC datasets. Together, we establish a key regulatory circuit, RICTOR-AKT-ZFX-UGCG-Ganglioside-EGFR-AKT, and elucidate its contribution to breast Cancer progression.

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