Epigenetic upregulation of Schlafen11 renders WNT-and SHH-Activated medulloblastomas sensitive to cisplatin

Satoshi Nakata; Junko Murai; Masayasu Okada; Haruhiko Takahashi; Tyler H. Findlay; Kristen Malebranche; Akhila Parthasarathy; Satoshi Miyashita; Ramil Gabdulkhaev; Ilan Benkimoun; Sabine Druillennec; Sara Chabi; Eleanor Hawkins; Hiroaki Miyahara; Kensuke Tateishi; Shinji Yamashita; Shiori Yamada; Taiki Saito; Jotaro On; Jun Watanabe; Yoshihiro Tsukamoto; Junichi Yoshimura; Makoto Oishi; Toshimichi Nakano; Masaru Imamura; Chihaya Imai; Tetsuya Yamamoto; Hideo Takeshima; Atsuo T. Sasaki; Fausto J. Rodriguez; Sumihito Nobusawa; Pascale Varlet; Celio Pouponnot; Satoru Osuka; Yves Pommier; Akiyoshi Kakita; Yukihiko Fujii; Eric H. Raabe; Charles G. Eberhart; Manabu Natsumeda

doi:10.1093/neuonc/noac243

Epigenetic upregulation of Schlafen11 renders WNT-and SHH-Activated medulloblastomas sensitive to cisplatin

Satoshi Nakata, Junko Murai, Masayasu Okada, Haruhiko Takahashi, Tyler H. Findlay, Kristen Malebranche, Akhila Parthasarathy, Satoshi Miyashita, Ramil Gabdulkhaev, Ilan Benkimoun, Sabine Druillennec, Sara Chabi, Eleanor Hawkins, Hiroaki Miyahara, Kensuke Tateishi, Shinji Yamashita, Shiori Yamada, Taiki Saito, Jotaro On, Jun WatanabeYoshihiro Tsukamoto, Junichi Yoshimura, Makoto Oishi, Toshimichi Nakano, Masaru Imamura, Chihaya Imai, Tetsuya Yamamoto, Hideo Takeshima, Atsuo T. Sasaki, Fausto J. Rodriguez, Sumihito Nobusawa, Pascale Varlet, Celio Pouponnot, Satoru Osuka, Yves Pommier, Akiyoshi Kakita, Yukihiko Fujii, Eric H. Raabe, Charles G. Eberhart, Manabu Natsumeda

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. Methods: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. Results: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-Activated subgroup and in a proportion of the SHH-Activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. Conclusions: High SLFN11 expression is one factor which renders favorable outcomes in WNT-Activated and a subset of SHH-Activated medulloblastoma possibly through enhancing response to cisplatin.

Original language	English (US)
Pages (from-to)	899-912
Number of pages	14
Journal	Neuro-oncology
Volume	25
Issue number	5
DOIs	https://doi.org/10.1093/neuonc/noac243
State	Published - May 1 2023

Keywords

DNA damaging agent
SLFN11
medulloblastoma

ASJC Scopus subject areas

Oncology
Clinical Neurology
Cancer Research

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10.1093/neuonc/noac243

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Nakata, S., Murai, J., Okada, M., Takahashi, H., Findlay, T. H., Malebranche, K., Parthasarathy, A., Miyashita, S., Gabdulkhaev, R., Benkimoun, I., Druillennec, S., Chabi, S., Hawkins, E., Miyahara, H., Tateishi, K., Yamashita, S., Yamada, S., Saito, T., On, J., ... Natsumeda, M. (2023). Epigenetic upregulation of Schlafen11 renders WNT-and SHH-Activated medulloblastomas sensitive to cisplatin. Neuro-oncology, 25(5), 899-912. https://doi.org/10.1093/neuonc/noac243

Nakata, S, Murai, J, Okada, M, Takahashi, H, Findlay, TH, Malebranche, K, Parthasarathy, A, Miyashita, S, Gabdulkhaev, R, Benkimoun, I, Druillennec, S, Chabi, S, Hawkins, E, Miyahara, H, Tateishi, K, Yamashita, S, Yamada, S, Saito, T, On, J, Watanabe, J, Tsukamoto, Y, Yoshimura, J, Oishi, M, Nakano, T, Imamura, M, Imai, C, Yamamoto, T, Takeshima, H, Sasaki, AT, Rodriguez, FJ, Nobusawa, S, Varlet, P, Pouponnot, C, Osuka, S, Pommier, Y, Kakita, A, Fujii, Y, Raabe, EH , Eberhart, CG & Natsumeda, M 2023, 'Epigenetic upregulation of Schlafen11 renders WNT-and SHH-Activated medulloblastomas sensitive to cisplatin', Neuro-oncology, vol. 25, no. 5, pp. 899-912. https://doi.org/10.1093/neuonc/noac243

@article{1f078f31899f440188a12f2b46b2b88e,

title = "Epigenetic upregulation of Schlafen11 renders WNT-and SHH-Activated medulloblastomas sensitive to cisplatin",

abstract = "Background: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. Methods: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. Results: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-Activated subgroup and in a proportion of the SHH-Activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. Conclusions: High SLFN11 expression is one factor which renders favorable outcomes in WNT-Activated and a subset of SHH-Activated medulloblastoma possibly through enhancing response to cisplatin.",

keywords = "DNA damaging agent, SLFN11, medulloblastoma",

author = "Satoshi Nakata and Junko Murai and Masayasu Okada and Haruhiko Takahashi and Findlay, {Tyler H.} and Kristen Malebranche and Akhila Parthasarathy and Satoshi Miyashita and Ramil Gabdulkhaev and Ilan Benkimoun and Sabine Druillennec and Sara Chabi and Eleanor Hawkins and Hiroaki Miyahara and Kensuke Tateishi and Shinji Yamashita and Shiori Yamada and Taiki Saito and Jotaro On and Jun Watanabe and Yoshihiro Tsukamoto and Junichi Yoshimura and Makoto Oishi and Toshimichi Nakano and Masaru Imamura and Chihaya Imai and Tetsuya Yamamoto and Hideo Takeshima and Sasaki, {Atsuo T.} and Rodriguez, {Fausto J.} and Sumihito Nobusawa and Pascale Varlet and Celio Pouponnot and Satoru Osuka and Yves Pommier and Akiyoshi Kakita and Yukihiko Fujii and Raabe, {Eric H.} and Eberhart, {Charles G.} and Manabu Natsumeda",

year = "2023",

month = may,

day = "1",

doi = "10.1093/neuonc/noac243",

language = "English (US)",

volume = "25",

pages = "899--912",

journal = "Neuro-oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "5",

}

TY - JOUR

T1 - Epigenetic upregulation of Schlafen11 renders WNT-and SHH-Activated medulloblastomas sensitive to cisplatin

AU - Nakata, Satoshi

AU - Murai, Junko

AU - Okada, Masayasu

AU - Takahashi, Haruhiko

AU - Findlay, Tyler H.

AU - Malebranche, Kristen

AU - Parthasarathy, Akhila

AU - Miyashita, Satoshi

AU - Gabdulkhaev, Ramil

AU - Benkimoun, Ilan

AU - Druillennec, Sabine

AU - Chabi, Sara

AU - Hawkins, Eleanor

AU - Miyahara, Hiroaki

AU - Tateishi, Kensuke

AU - Yamashita, Shinji

AU - Yamada, Shiori

AU - Saito, Taiki

AU - On, Jotaro

AU - Watanabe, Jun

AU - Tsukamoto, Yoshihiro

AU - Yoshimura, Junichi

AU - Oishi, Makoto

AU - Nakano, Toshimichi

AU - Imamura, Masaru

AU - Imai, Chihaya

AU - Yamamoto, Tetsuya

AU - Takeshima, Hideo

AU - Sasaki, Atsuo T.

AU - Rodriguez, Fausto J.

AU - Nobusawa, Sumihito

AU - Varlet, Pascale

AU - Pouponnot, Celio

AU - Osuka, Satoru

AU - Pommier, Yves

AU - Kakita, Akiyoshi

AU - Fujii, Yukihiko

AU - Raabe, Eric H.

AU - Eberhart, Charles G.

AU - Natsumeda, Manabu

PY - 2023/5/1

Y1 - 2023/5/1

N2 - Background: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. Methods: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. Results: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-Activated subgroup and in a proportion of the SHH-Activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. Conclusions: High SLFN11 expression is one factor which renders favorable outcomes in WNT-Activated and a subset of SHH-Activated medulloblastoma possibly through enhancing response to cisplatin.

AB - Background: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. Methods: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. Results: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-Activated subgroup and in a proportion of the SHH-Activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. Conclusions: High SLFN11 expression is one factor which renders favorable outcomes in WNT-Activated and a subset of SHH-Activated medulloblastoma possibly through enhancing response to cisplatin.

KW - DNA damaging agent

KW - SLFN11

KW - medulloblastoma

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U2 - 10.1093/neuonc/noac243

DO - 10.1093/neuonc/noac243

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SN - 1522-8517

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JO - Neuro-oncology

JF - Neuro-oncology

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ER -

Epigenetic upregulation of Schlafen11 renders WNT-and SHH-Activated medulloblastomas sensitive to cisplatin

Abstract

Keywords

ASJC Scopus subject areas

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