PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells

Meng Hsun Hsieh; Yi Ting Chen; You Tzung Chen; Yi Hsuan Lee; Jean Lu; Chung Liang Chien; Hsin Fu Chen; Hong Nerng Ho; Chia Jung Yu; Zhao Qi Wang; Shu Chun Teng

doi:10.1093/nar/gkx683

PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells

Meng Hsun Hsieh, Yi Ting Chen, You Tzung Chen, Yi Hsuan Lee, Jean Lu, Chung Liang Chien, Hsin Fu Chen, Hong Nerng Ho, Chia Jung Yu, Zhao Qi Wang, Shu Chun Teng

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

40 Citations (Scopus)

Abstract

Telomerase is highly expressed in cancer and embryonic stem cells (ESCs) and implicated in controlling genome integrity, cancer formation and stemness. Previous studies identified that Krüppel-like transcription factor 4 (KLF4) activates telomerase reverse transcriptase (TERT) expression and contributes to the maintenance of self-renewal in ESCs. However, little is known about how KLF4 regulates TERT expression. Here, we discover poly(ADP-ribose) polymerase 1 (PARP1) as a novel KLF4-interacting partner. Knockdown of PARP1 reduces TERT expression and telomerase activity not only in cancer cells, but also in human and mouse ESCs. Recruitment of KLF4 to TERT promoter is reduced in PARP1-suppressed cells. The poly(ADP-ribose) polymerase activity is dispensable, while the oligo(ADP-ribose) polymerase activity is required for the PARP1- and KLF4-mediated TERTactivation. Repression of Parp1 in mouse ESCs decreases expression of pluripotent markers and induces differentiation. These results suggest that PARP1 recruits KLF4 to activate telomerase expression and stem cell pluripotency, indicating a positive regulatory role of the PARP1-KLF4 complex in telomerase expression in cancer and stem cells.

Original language	English
Pages (from-to)	10492-10503
Number of pages	12
Journal	Nucleic Acids Research
Volume	45
Issue number	18
DOIs	https://doi.org/10.1093/nar/gkx683
Publication status	Published - Oct 1 2017
Externally published	Yes

ASJC Scopus subject areas

Genetics

UN SDGs

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

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10.1093/nar/gkx683

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title = "PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells",

abstract = "Telomerase is highly expressed in cancer and embryonic stem cells (ESCs) and implicated in controlling genome integrity, cancer formation and stemness. Previous studies identified that Kr{\"u}ppel-like transcription factor 4 (KLF4) activates telomerase reverse transcriptase (TERT) expression and contributes to the maintenance of self-renewal in ESCs. However, little is known about how KLF4 regulates TERT expression. Here, we discover poly(ADP-ribose) polymerase 1 (PARP1) as a novel KLF4-interacting partner. Knockdown of PARP1 reduces TERT expression and telomerase activity not only in cancer cells, but also in human and mouse ESCs. Recruitment of KLF4 to TERT promoter is reduced in PARP1-suppressed cells. The poly(ADP-ribose) polymerase activity is dispensable, while the oligo(ADP-ribose) polymerase activity is required for the PARP1- and KLF4-mediated TERTactivation. Repression of Parp1 in mouse ESCs decreases expression of pluripotent markers and induces differentiation. These results suggest that PARP1 recruits KLF4 to activate telomerase expression and stem cell pluripotency, indicating a positive regulatory role of the PARP1-KLF4 complex in telomerase expression in cancer and stem cells.",

author = "Hsieh, {Meng Hsun} and Chen, {Yi Ting} and Chen, {You Tzung} and Lee, {Yi Hsuan} and Jean Lu and Chien, {Chung Liang} and Chen, {Hsin Fu} and Ho, {Hong Nerng} and Yu, {Chia Jung} and Wang, {Zhao Qi} and Teng, {Shu Chun}",

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doi = "10.1093/nar/gkx683",

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T1 - PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells

AU - Hsieh, Meng Hsun

AU - Chen, Yi Ting

AU - Chen, You Tzung

AU - Lee, Yi Hsuan

AU - Lu, Jean

AU - Chien, Chung Liang

AU - Chen, Hsin Fu

AU - Ho, Hong Nerng

AU - Yu, Chia Jung

AU - Wang, Zhao Qi

AU - Teng, Shu Chun

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Telomerase is highly expressed in cancer and embryonic stem cells (ESCs) and implicated in controlling genome integrity, cancer formation and stemness. Previous studies identified that Krüppel-like transcription factor 4 (KLF4) activates telomerase reverse transcriptase (TERT) expression and contributes to the maintenance of self-renewal in ESCs. However, little is known about how KLF4 regulates TERT expression. Here, we discover poly(ADP-ribose) polymerase 1 (PARP1) as a novel KLF4-interacting partner. Knockdown of PARP1 reduces TERT expression and telomerase activity not only in cancer cells, but also in human and mouse ESCs. Recruitment of KLF4 to TERT promoter is reduced in PARP1-suppressed cells. The poly(ADP-ribose) polymerase activity is dispensable, while the oligo(ADP-ribose) polymerase activity is required for the PARP1- and KLF4-mediated TERTactivation. Repression of Parp1 in mouse ESCs decreases expression of pluripotent markers and induces differentiation. These results suggest that PARP1 recruits KLF4 to activate telomerase expression and stem cell pluripotency, indicating a positive regulatory role of the PARP1-KLF4 complex in telomerase expression in cancer and stem cells.

AB - Telomerase is highly expressed in cancer and embryonic stem cells (ESCs) and implicated in controlling genome integrity, cancer formation and stemness. Previous studies identified that Krüppel-like transcription factor 4 (KLF4) activates telomerase reverse transcriptase (TERT) expression and contributes to the maintenance of self-renewal in ESCs. However, little is known about how KLF4 regulates TERT expression. Here, we discover poly(ADP-ribose) polymerase 1 (PARP1) as a novel KLF4-interacting partner. Knockdown of PARP1 reduces TERT expression and telomerase activity not only in cancer cells, but also in human and mouse ESCs. Recruitment of KLF4 to TERT promoter is reduced in PARP1-suppressed cells. The poly(ADP-ribose) polymerase activity is dispensable, while the oligo(ADP-ribose) polymerase activity is required for the PARP1- and KLF4-mediated TERTactivation. Repression of Parp1 in mouse ESCs decreases expression of pluripotent markers and induces differentiation. These results suggest that PARP1 recruits KLF4 to activate telomerase expression and stem cell pluripotency, indicating a positive regulatory role of the PARP1-KLF4 complex in telomerase expression in cancer and stem cells.

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PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells

Abstract

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