Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance

TY - JOUR

T1 - Contribution of STAT3 and RAD23B in Primary Sézary Cells to Histone Deacetylase Inhibitor FK228 Resistance

AU - Butler, Rosie M.

AU - Mckenzie, Robert C.

AU - Jones, Christine L.

AU - Flanagan, Charlotte E.

AU - Woollard, Wesley J.

AU - Demontis, Maria

AU - Ferreira, Silvia

AU - Tosi, Isabella

AU - John, Susan

AU - Whittaker, Sean J.

AU - Mitchell, Tracey J.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - FK228 (romidepsin) and suberoylanilide hydroxamic acid (vorinostat) are histone deacetylase inhibitors (HDACi) approved by the US Food and Drug Administration for cutaneous T-cell lymphoma (CTCL), including the leukemic subtype Sézary syndrome. This study investigates RAD23B and STAT3 gene perturbations in a large cohort of primary Sézary cells and the effect of FK228 treatment on tyrosine phosphorylation of STAT3 (pYSTAT3) and RAD23B expression. We report RAD23B copy number variation in 10% (12/119, P ≤ 0.01) of SS patients, associated with reduced mRNA expression (P = 0.04). RAD23B knockdown in a CTCL cell line led to a reduction in FK228-induced apoptosis. Histone deacetylase inhibitor treatment significantly reduced pYSTAT3 in primary Sézary cells and was partially mediated by RAD23B. A distinct pattern of RAD23B-pYSTAT3 co-expression in primary Sézary cells was detected. Critically, Sézary cells harboring the common STAT3 Y640F variant were less sensitive to FK228-induced apoptosis and exogenous expression of STAT3 Y640F, and D661Y conferred partial resistance to STAT3 transcriptional inhibition by FK228 (P ≤ 0.0024). These findings suggest that RAD23B and STAT3 gene perturbations could reduce sensitivity to histone deacetylase inhibitors in SS patients.

AB - FK228 (romidepsin) and suberoylanilide hydroxamic acid (vorinostat) are histone deacetylase inhibitors (HDACi) approved by the US Food and Drug Administration for cutaneous T-cell lymphoma (CTCL), including the leukemic subtype Sézary syndrome. This study investigates RAD23B and STAT3 gene perturbations in a large cohort of primary Sézary cells and the effect of FK228 treatment on tyrosine phosphorylation of STAT3 (pYSTAT3) and RAD23B expression. We report RAD23B copy number variation in 10% (12/119, P ≤ 0.01) of SS patients, associated with reduced mRNA expression (P = 0.04). RAD23B knockdown in a CTCL cell line led to a reduction in FK228-induced apoptosis. Histone deacetylase inhibitor treatment significantly reduced pYSTAT3 in primary Sézary cells and was partially mediated by RAD23B. A distinct pattern of RAD23B-pYSTAT3 co-expression in primary Sézary cells was detected. Critically, Sézary cells harboring the common STAT3 Y640F variant were less sensitive to FK228-induced apoptosis and exogenous expression of STAT3 Y640F, and D661Y conferred partial resistance to STAT3 transcriptional inhibition by FK228 (P ≤ 0.0024). These findings suggest that RAD23B and STAT3 gene perturbations could reduce sensitivity to histone deacetylase inhibitors in SS patients.

KW - HDACi, STAT3, RAD23, Sezary Syndrome, CTCL, JAK, primary T cells

UR - http://www.scopus.com/inward/record.url?scp=85065541166&partnerID=8YFLogxK

U2 - 10.1016/j.jid.2019.03.1130

DO - 10.1016/j.jid.2019.03.1130

M3 - Article

SN - 0022-202X

VL - 139

SP - 1975-1984.e2

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 9

ER -