Effects of ICMT and antioxidants on cancer development

We then identified INPP5E as an ICMT-dependent substrate. ICMT inhibition reduced INPP5E methylation and membrane localization and increased PI(4,5)P2 at the plasma membrane. Restoring INPP5E to the membrane partly rescued growth defects caused by ICMT suppression.

These results indicate that BRAFⱽ⁶⁰⁰ᴱ-driven melanoma depends on ICMT partly because ICMT maintains the membrane localization and function of INPP5E.</p><p dir="ltr">In <b>Paper II</b>, we investigated how antioxidants influence tumor angiogenesis. We found that the redox-sensitive transcription factor BACH1 regulates a broad angiogenic gene program. Under normoxia, antioxidants increased BACH1 expression and induced angiogenesis-related gene expression in lung cancer cells and tumor organoids, with similar effects in xenograft tumors.

Hypoxia also increased BACH1 expression. HIFla contributed to this increase, but BACH1 could still activate angiogenesis-related genes in the absence of HIFla. Antioxidant treatment increased tumor vascularity, and this effect depended on BACH1.

Tumors with increased BACH1 were more sensitive to VEGFR2-targeted treatment, and BACH1 expression was associated with angiogenesis markers in human lung cancers. These results show that BACH1 links redox and oxygen conditions to the regulation of tumor angiogenesis.</p><p dir="ltr">In <b>Paper III</b>, we examined whether long-term antioxidant exposure affects spontaneous tumor development in wild-type mice. Lifelong dietary supplementation with vitamin E or ß-carotene, beginning during gestation, increased the incidence and number of gross tumors in FVB/N mice; the effect was smaller in C57BL/6N mice.

Tumors developed in several organs, with the lung being the most affected in FVB/N mice. In parallel, primary FVB/N mouse embryonic fibroblasts exposed to Trolox, a water-soluble vitamin E analog, during long-term culture showed persistent increases in proliferation and anchorage-independent growth. Only Trolox-exposed cells formed tumors after transplantation into NSG mice, without further Trolox administration.

At 6 months, RNA sequencing and follow-up experiments showed reduced p53-associated transcription and broader changes in proliferation and stress-response programs. These findings show that sustained antioxidant exposure can promote spontaneous tumor development in susceptible mouse backgrounds and favor persistent transformation-associated changes in primary cells.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. ICMT supports BRAFV600E-driven tumor growth by membrane targeting of the CAAX protein INPP5E<b>. </b><b>Yang, X.</b>, Qiao, X., Schmidt, S., Eklund, E. A., Ebner-Walter, C., Ivarsson, E., Crespo, M. A., Kersemakers, N., Dzanan, J. J., Thorisson, B., Lundgren, C., Lim, H. C., Shkoukani, S., Tüksammel, E., Xu, X., Sayin, V. I., Martín-Fontecha, M., Ortega-Gutiérrez, S., Dalin, M., & Bergo, M. O. (2026).

Proceedings of the National Academy of Sciences of the United States of America, 123(20), e2601795123. <a href="doi.org/10.1073/pnas.2601795123" target="_blank" rel="noreferrer">doi.org/10.1073/pnas.2601795123</a></p><p dir="ltr">II. Antioxidants stimulate BACH1-dependent tumor angiogenesis. Wang, T., Dong, Y., Huang, Z., Zhang, G., Zhao, Y., Yao, H., Hu, J., Tüksammel, E., Cai, H., Liang, N., Xu, X., <b>Yang, X.</b>, Schmidt, S., Qiao, X., Schlisio, S., Strömblad, S., Qian, H., Jiang, C., Treuter, E., & Bergo, M. O. (2023).

The Journal of Clinical Investigation, 133(20), e169671. <a href="doi.org/10.1172/JCI169671" target="_blank" rel="noreferrer">doi.org/10.1172/JCI169671</a></p><p dir="ltr">III. Long-term antioxidant administration increases spontaneous tumor development in FVB/N mice<b>. </b><b>Yang, X.</b>, Wiel, C., Qiao, X., Ebner-Walter, C., Crespo, M. A., Xie, G., Tüksammel, E., Schmidt, S., Xu, X., Lehmann, S., & Bergo, M. O. [Manuscript]</p>