Glioblastoma is the most common form of primary brain cancer and remains one of the deadliest of human cancers with near-uniform fatality. Increasing evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells with self-renew ability and tumorigenicity, termed as tumor initiating cells. The mechanism how the tumor initiating cells maintain and gain tumorigenicity in glioblastoma still remains unclear.
Here, we used sphere formation and tumor propagating potential to measure the tumorigenicity in established cell line and primary glioblastoma cells. The results indicated that glioblastoma tumorigenicity appears largely deterministic, though spontaneous gain and loss of this property occur at low frequency. Mechanically, this dynamic transition in tumorigenicity was governed by MYC level which was modulated epigenetically by the lysine-specific demethylase 1 (LSD1). Elevated MYC expression, in turn, regulates OLIG2, SOX2 and POU3F2, a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors facilitates transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.
Importantly, the effect of LSD1 on tumorigenity is “Janus”-like; partial depletion of LSD1 caused increased MYC expression and a pro-tumorigenic state. In contrast, complete suppression of LSD1 induced cell death. As such, therapeutic strategies targeting LSD1 and other targets manifesting similar “Janus” effect should be designed to prevent unintended induction of tumorigenesis during treatment.
Citation Format: Jie Li, David Kozono, Masayuki Nitta, Oltea Sampetrean, David Gonda, Deepa S. Kushwaha, Dmitry Merzon, Valya Ramakrishnan, Shan Zhu, Kaya Zhu, Hiroko Matsui, Olivier Harismendy, Wei Hua, Ying Mao, Chang-Hyuk Kwon, Hideyuki Saya, Bob S. Carter, Donald P. Pizzo, Scott R. VandenBerg, Clark C. Chen. Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 979. doi:10.1158/1538-7445.AM2015-979