Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells

Yijun Yang; Silvia Anahi Valdés-Rives; Qing Liu; Tong Gao; Chakkapong Burudpakdee; Yuzhe Li; Jun Tan; Yinfei Tan; Christian A. Koch; Yuan Rong; Steven R. Houser; Shuanzeng Wei; Kathy Q. Cai; Jinhua Wu; Sheue yann Cheng; Robert Wechsler-Reya; Zeng jie Yang

doi:10.1016/j.ccell.2024.07.008

Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells

Yijun Yang, Silvia Anahi Valdés-Rives, Qing Liu, Tong Gao, Chakkapong Burudpakdee, Yuzhe Li, Jun Tan, Yinfei Tan, Christian A. Koch, Yuan Rong, Steven R. Houser, Shuanzeng Wei, Kathy Q. Cai, Jinhua Wu, Sheue yann Cheng, Robert Wechsler-Reya, Zeng jie Yang

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

2 Scopus citations

Abstract

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

Original language	English
Pages (from-to)	1434-1449.e5
Journal	Cancer Cell
Volume	42
Issue number	8
DOIs	https://doi.org/10.1016/j.ccell.2024.07.008
State	Published - Aug 12 2024

Keywords

EZH2
NeuroD1
TRα1
differentiation therapy
epigenetic regulation
hypothyroidism
medulloblastoma
terminal differentiation
thyroid hormone
Cell Differentiation/drug effects
Humans
Gene Expression Regulation, Neoplastic/drug effects
Thyroid Hormones/metabolism
Signal Transduction/drug effects
Disease Progression
Enhancer of Zeste Homolog 2 Protein/metabolism
Basic Helix-Loop-Helix Transcription Factors/metabolism
Animals
Cell Line, Tumor
Medulloblastoma/pathology
Mice
Cerebellar Neoplasms/pathology
Thyroid Hormone Receptors alpha/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2024.07.008

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Yang, Y., Valdés-Rives, S. A., Liu, Q., Gao, T., Burudpakdee, C., Li, Y., Tan, J., Tan, Y., Koch, C. A., Rong, Y., Houser, S. R., Wei, S., Cai, K. Q., Wu, J., Cheng, S. Y., Wechsler-Reya, R., & Yang, Z. J. (2024). Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells. Cancer Cell, 42(8), 1434-1449.e5. https://doi.org/10.1016/j.ccell.2024.07.008

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title = "Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells",

abstract = "Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.",

keywords = "EZH2, NeuroD1, TRα1, differentiation therapy, epigenetic regulation, hypothyroidism, medulloblastoma, terminal differentiation, thyroid hormone, Cell Differentiation/drug effects, Humans, Gene Expression Regulation, Neoplastic/drug effects, Thyroid Hormones/metabolism, Signal Transduction/drug effects, Disease Progression, Enhancer of Zeste Homolog 2 Protein/metabolism, Basic Helix-Loop-Helix Transcription Factors/metabolism, Animals, Cell Line, Tumor, Medulloblastoma/pathology, Mice, Cerebellar Neoplasms/pathology, Thyroid Hormone Receptors alpha/metabolism",

author = "Yijun Yang and Vald{\'e}s-Rives, {Silvia Anahi} and Qing Liu and Tong Gao and Chakkapong Burudpakdee and Yuzhe Li and Jun Tan and Yinfei Tan and Koch, {Christian A.} and Yuan Rong and Houser, {Steven R.} and Shuanzeng Wei and Cai, {Kathy Q.} and Jinhua Wu and Cheng, {Sheue yann} and Robert Wechsler-Reya and Yang, {Zeng jie}",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = aug,

day = "12",

doi = "10.1016/j.ccell.2024.07.008",

language = "English",

volume = "42",

pages = "1434--1449.e5",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "8",

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Yang, Y, Valdés-Rives, SA, Liu, Q, Gao, T, Burudpakdee, C, Li, Y, Tan, J, Tan, Y, Koch, CA, Rong, Y, Houser, SR, Wei, S , Cai, KQ , Wu, J, Cheng, SY, Wechsler-Reya, R & Yang, ZJ 2024, 'Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells', Cancer Cell, vol. 42, no. 8, pp. 1434-1449.e5. https://doi.org/10.1016/j.ccell.2024.07.008

TY - JOUR

T1 - Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells

AU - Yang, Yijun

AU - Valdés-Rives, Silvia Anahi

AU - Liu, Qing

AU - Gao, Tong

AU - Burudpakdee, Chakkapong

AU - Li, Yuzhe

AU - Tan, Jun

AU - Tan, Yinfei

AU - Koch, Christian A.

AU - Rong, Yuan

AU - Houser, Steven R.

AU - Wei, Shuanzeng

AU - Cai, Kathy Q.

AU - Wu, Jinhua

AU - Cheng, Sheue yann

AU - Wechsler-Reya, Robert

AU - Yang, Zeng jie

PY - 2024/8/12

Y1 - 2024/8/12

N2 - Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

AB - Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

KW - EZH2

KW - NeuroD1

KW - TRα1

KW - differentiation therapy

KW - epigenetic regulation

KW - hypothyroidism

KW - medulloblastoma

KW - terminal differentiation

KW - thyroid hormone

KW - Cell Differentiation/drug effects

KW - Humans

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Thyroid Hormones/metabolism

KW - Signal Transduction/drug effects

KW - Disease Progression

KW - Enhancer of Zeste Homolog 2 Protein/metabolism

KW - Basic Helix-Loop-Helix Transcription Factors/metabolism

KW - Animals

KW - Cell Line, Tumor

KW - Medulloblastoma/pathology

KW - Mice

KW - Cerebellar Neoplasms/pathology

KW - Thyroid Hormone Receptors alpha/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85200538611&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2024.07.008

DO - 10.1016/j.ccell.2024.07.008

M3 - Article

C2 - 39137728

AN - SCOPUS:85200538611

SN - 1535-6108

VL - 42

SP - 1434-1449.e5

JO - Cancer Cell

JF - Cancer Cell

IS - 8

ER -

Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells

Abstract

Keywords

UN SDGs

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