Targeting B7‑H3 through EZH2 inhibition in MYC‑positive Group 3 medulloblastoma

  • Authors:
    • Katherine Shishido
    • Ian J. Purvis
    • Kiran K. Velpula
    • Sujatha Venkataraman
    • Rajeev Vibhakar
    • Swapna Asuthkar
  • View Affiliations

  • Published online on: April 27, 2023     https://doi.org/10.3892/or.2023.8556
  • Article Number: 119
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Abstract

The most aggressive subtype of medulloblastoma (MB), Group 3, is characterized by MYC amplifications. However, targeting MYC has proven unsuccessful, and there remains a lack of therapeutic targets for treating MB. Studies have shown that the B7 homolog 3 (B7‑H3) promotes cell proliferation and tumor cell invasion in a variety of cancers. Similarly, it was recently revealed that B7‑H3 promotes angiogenesis in Group 3 MB and likely facilitates MB metastasis through exosome biogenesis. While therapies targeting B7‑H3 remain in the early stages of development, targeting upstream regulators of B7‑H3 expression may be more effective for halting MB progression. Notably, MYC and the enhancer of zeste homolog 2 (EZH2) are known to regulate B7‑H3 expression, and a previous study by the authors suggested that B7‑H3 amplifications present in MB are likely the result of EZH2‑MYC mediated activities. In the present study, it was reported that overexpression of EZH2 is associated with lower overall survival in Group 3 MB patients. It was also revealed that inhibition of EZH2 significantly reduces B7‑H3 and MYC transcript levels and upregulates miR‑29a, indicating that EZH2 post‑transcriptionally regulates B7‑H3 expression in Group 3 MB cells. Pharmacological inhibition of EZH2 using EPZ005687 attenuated MB cell viability and reduced the expression of B7‑H3. Similarly, pharmacological inhibition and knockdown of EZH2 led to the downregulation of MYC, B7‑H3, and H3K27me3. Further, EZH2 silencing induced apoptosis and reduced colony‑forming ability in MB cells, whereas EZH2 inhibition in MYC‑amplified C17.2 neural stem cells induced G2/M phase arrest while downregulating B7‑H3 expression. Collectively, the current study positions EZH2 as a viable target for the future development of MB treatments and that targeting EZH2 in combination with B7‑H3 immunotherapy may be an effective treatment for halting MB progression.

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June-2023
Volume 49 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Shishido K, Purvis IJ, Velpula KK, Venkataraman S, Vibhakar R and Asuthkar S: Targeting B7‑H3 through EZH2 inhibition in MYC‑positive Group 3 medulloblastoma. Oncol Rep 49: 119, 2023.
APA
Shishido, K., Purvis, I.J., Velpula, K.K., Venkataraman, S., Vibhakar, R., & Asuthkar, S. (2023). Targeting B7‑H3 through EZH2 inhibition in MYC‑positive Group 3 medulloblastoma. Oncology Reports, 49, 119. https://doi.org/10.3892/or.2023.8556
MLA
Shishido, K., Purvis, I. J., Velpula, K. K., Venkataraman, S., Vibhakar, R., Asuthkar, S."Targeting B7‑H3 through EZH2 inhibition in MYC‑positive Group 3 medulloblastoma". Oncology Reports 49.6 (2023): 119.
Chicago
Shishido, K., Purvis, I. J., Velpula, K. K., Venkataraman, S., Vibhakar, R., Asuthkar, S."Targeting B7‑H3 through EZH2 inhibition in MYC‑positive Group 3 medulloblastoma". Oncology Reports 49, no. 6 (2023): 119. https://doi.org/10.3892/or.2023.8556