Open AccessCrosstalk between hnRNP K and SET in ATRA‐induced differentiation in acute promyelocytic leukemia
Author(s) -
Padovani Karina Stringhetta,
Goto Renata Nishida,
Fugio Lais Brigliadori,
Garcia Cristiana Bernadelli,
Alves Vani Maria,
Brassesco Maria Sol,
Greene Lewis Joel,
Rego Eduardo Magalhães,
Leopoldino Andréia Machado
Publication year - 2021
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.13210
Subject(s) - acute promyelocytic leukemia , arsenic trioxide , gene knockdown , promyelocytic leukemia protein , cancer research , tretinoin , biology , heterogeneous nuclear ribonucleoprotein , microbiology and biotechnology , retinoic acid , apoptosis , chemistry , cell culture , ribonucleoprotein , biochemistry , rna , genetics , gene
HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all‐trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA‐induced differentiation in APL. We observed higher (5‐ to 40‐fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short‐hairpin RNA led to cell death in ATRA‐sensitive NB4 and resistant NB4‐R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4‐R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis‐specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4‐R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4‐R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance.