Crenigacestat | Glucocorticoidrecep Signal

Epigenetic Profiling Identifies LIF as a Super-enhancer-Controlled Regulator of Stem Cell-like Properties in Osteosarcoma
Bing Lu # 1 2, Yangyang He # 1 2, Jincan He 1 2, Li Wang 1 2, Zhenguo Liu 3, Jiayan Yang 1 2, Zhuoxing Gao 1 2, Guohao Lu 1 2, Changye Zou 4, Wei Zhao 5 2

We further investigated the functional consequence of LIF/STAT3 signaling 5D, qPCR results confirmed that recombinant LIF protein treated cells had

NOTCH1 signature gene expression in osteosarcoma cells. To investigate the role of
NOTCH1 in UTX-LIF stemness-related effect, we detected the NOTCH1 signaling
gene expression with GSK-J4 or/and LIF. Our results demonstrated the LIF restored
the NOTCH1 signaling genes expression which has been interrupted by GSK-J4
treatment (Fig. 5E).
NOTCH1 inhibitor disrupts LIF dependent stemness transcription program
The effect of LIF inhibition on osteosarcoma cell stemness was confirmed by
subcutaneous injection of sphere-derived SJSA1 cells mixed with Matrigel into nude
mice treated with or without GSK-J4. As shown in Fig. 6A, the larger tumors formed
after vehicle treatment than those treated by GSK-J4. No significant change was noted
in the weight of GSK-J4-treated mice during 18 days of observation when compared
to control mice (Supplementary Fig. S6A). In addition, we injected sphere-derived
SJSA1 cells into the central cavity of the bone of immune-compromised mice
orthotopically. At week 3 after inoculation, mice with GSK-J4-treated group
developed smaller primary tumors than the vehicle-treated groups (Fig. 6B).
For assessing the consequence of NOTCH1 inhibition as a therapeutic rationale to
suppress osteosarcoma stemness, we monitored the expression of specific
stemness-related genes such as SOX2, OCT4, NANOG, and CD133 in LIF-treated
osteosarcoma tissues together with NOTCH1 inhibitor (Crenigacestat) (Fig. 6C).
NOTCH1 signaling pathway gene levels were reduced in Crenigacestat treated tissues
compared with control tissues (Supplementary Fig. S6B). Importantly, we observed
a dramatic decrease in SOX2, OCT4, NANOG, and CD133 levels of LIF treated
osteosarcoma tumor tissues after Crenigacestat treatment (Fig. 6D).

mortality and morbidity in adolescents. Although drug resistance is a common

and targeting the OSC population may prevent relapse and progression of

The present study advances the molecular insight on SEs responsible for

In this study, we also demonstrated that GSK-J4 decreases expression of

Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia. Cancer cell

journal of the American Society of Clinical Oncology 2002;20(3):776-90 doi

A. Enhancer regions are plotted in an increasing order based on their

Author Manuscript Published OnlineFirst on October 15, 2019; DOI: 10.1158/1541-7786.MCR-19-0470
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Epigenetic profiling identifies LIF as a super-enhancer controlled regulator of stem cell-like properties in osteosarcoma

Bing Lu, Yangyang He, Jincan He, et al.

Mol Cancer Res Published OnlineFirst October 15, 2019.

Updated version Access the most recent version of this article at:
doi:10.1158/1541-7786.MCR-19-0470
Supplementary Access the most recent supplemental material at:
Material http://mcr.aacrjournals.org/content/suppl/2019/10/15/1541-7786.MCR-19-0470.DC1
Author Author manuscripts have been peer reviewed and accepted for publication but have not yet
Manuscript been edited.

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