CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells

Pratheeshkumar, Poyil; Siraj, Abdul K.; Divya, Sasidharan Padmaja; Parvathareddy, Sandeep Kumar; Alobaisi, Khadija; Al-Sobhi, Saif S.; Al-Dayel, Fouad; Al-Kuraya, Khawla S.

doi:10.3390/ijms22020504

Open AccessArticle

CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells

by

Poyil Pratheeshkumar

^1,†

,

Abdul K. Siraj

^1,†,

Sasidharan Padmaja Divya

^1,†,

Sandeep Kumar Parvathareddy

¹,

Khadija Alobaisi

¹,

Saif S. Al-Sobhi

²,

Fouad Al-Dayel

³ and

Khawla S. Al-Kuraya

^1,*

¹

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia

²

Department of Surgery, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia

³

Department of Pathology, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2021, 22(2), 504; https://doi.org/10.3390/ijms22020504

Submission received: 2 December 2020 / Revised: 31 December 2020 / Accepted: 1 January 2021 / Published: 6 January 2021

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Abstract

Chromodomain-helicase-DNA-binding protein 4 (CHD4), a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex is highly expressed in several cancers. However, its role in the pathogenesis and progression of papillary thyroid carcinoma (PTC) has not been investigated. We investigated the prognostic significance of CHD4 in a large cohort of Middle Eastern PTC patients and explored the functional role of CHD4 in regulating cancer stemness and EMT in PTC cells. CHD4 overexpression was observed in 45.3% (650/1436) of PTCs, and was associated with aggressive clinico-pathological parameters and worse outcome. Functional analysis using PTC cell lines showed that forced expression of CHD4 promoted cell proliferation, spheroid growth, migration, invasion and progression of epithelial to mesenchymal transition (EMT) in PTC cells whereas its knockdown reversed the effect. Methylation of E-cadherin was associated with loss of expression in CHD4 expressing cells, while CHD4 depletion reactivated E-cadherin expression. Most importantly, knockdown of mesenchymal transcriptional factors, Snail1 or Zeb1, attenuated the spheroid growth in CHD4 expressing PTC cells, showing a potential link between EMT activation and stemness maintenance in PTC. These findings suggest that CHD4 might be a promising therapeutic target in the treatment of patients with an aggressive subtype of PTC.

Keywords: papillary thyroid carcinoma; CHD4; disease free survival; cancer stemness; EMT

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MDPI and ACS Style

Pratheeshkumar, P.; Siraj, A.K.; Divya, S.P.; Parvathareddy, S.K.; Alobaisi, K.; Al-Sobhi, S.S.; Al-Dayel, F.; Al-Kuraya, K.S. CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells. Int. J. Mol. Sci. 2021, 22, 504. https://doi.org/10.3390/ijms22020504

AMA Style

Pratheeshkumar P, Siraj AK, Divya SP, Parvathareddy SK, Alobaisi K, Al-Sobhi SS, Al-Dayel F, Al-Kuraya KS. CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells. International Journal of Molecular Sciences. 2021; 22(2):504. https://doi.org/10.3390/ijms22020504

Chicago/Turabian Style

Pratheeshkumar, Poyil, Abdul K. Siraj, Sasidharan Padmaja Divya, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Saif S. Al-Sobhi, Fouad Al-Dayel, and Khawla S. Al-Kuraya. 2021. "CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells" International Journal of Molecular Sciences 22, no. 2: 504. https://doi.org/10.3390/ijms22020504

APA Style

Pratheeshkumar, P., Siraj, A. K., Divya, S. P., Parvathareddy, S. K., Alobaisi, K., Al-Sobhi, S. S., Al-Dayel, F., & Al-Kuraya, K. S. (2021). CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells. International Journal of Molecular Sciences, 22(2), 504. https://doi.org/10.3390/ijms22020504

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CHD4 Predicts Aggressiveness in PTC Patients and Promotes Cancer Stemness and EMT in PTC Cells

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