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miR-133b suppresses colorectal cancer cell stemness and chemoresistance by targeting methyltransferase DOT1L.

Abstract：

:Cancer stem cells (CSCs) are a subpopulation of chemoresistant cells that play a critical role in disease recurrence following chemotherapy. It has been reported that microRNA-133b (miR-133b) acts as a tumor suppressor in colorectal cancer (CRC). However, whether miR-133b is associated with CRC stemness and chemoresistance is not clear. In this study, we report that miR-133b is downregulated in colorectal spheroids, which are enriched with CSCs and display stem cell-like characteristics, including upreulation of CSCs surface markers and elevated chemoresistance. Additionally, miR-133b overexpression reduces CRC stemness and overrides chemoresistance to 5-Fluorouracil (5-FU) and oxaliplatin (OXP), indicating a negative role of miR-133b in regulating CRC stemness and chemoresistance. Moreover, miR-133b directly targets and suppresses the expression of disruptor of telomeric silencing 1-like (DOT1L), an exclusive H3K79 methyltransferase. Furthermore, miR-133b overexpression suppresses DOT1L-mediated H3K79me2 modification of stem cell genes, which is consistent with their downregulated transcription. More importantly, DOT1L restoration abrogates the suppressive effects of miR-133b on CRC stemness and chemoresistance, hence demonstrating that miR-133b regulates CRC stemness and chemoresistance through targeting DOT1L. Overall, these results imply that miR-133b might represent a novel therapeutic target in interfering CRC stemness and chemoresistance.

journal_name

Exp Cell Res

journal_title

Experimental cell research

authors

Lv L,Li Q,Chen S,Zhang X,Tao X,Tang X,Wang S,Che G,Yu Y,He L

doi

10.1016/j.yexcr.2019.111597

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

111597

issue

1

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(19)30454-9

journal_volume

385

pub_type

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