Crosstalk between hnRNP K and SET in ATRA-induced differentiation in acute promyelocytic leukemia

Author(s)

Padovani, Karina Stringhetta ^{[1, 2]} ; Goto, Renata Nishida ^[1] ; Fugio, Lais Brigliadori ^[1] ; Garcia, Cristiana Bernadelli ^[1] ; Alves, Vani Maria ^[3] ; Brassesco, Maria Sol ^[4] ; Greene, Lewis Joel ^{[2, 3]} ; Rego, Eduardo Magalhaes ^{[2, 5]} ; Leopoldino, Andreia Machado ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Toxicol & Food Sci, Av Cafe S-N, Bloco A, Sala 99A, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Reg Blood Ctr Ribeirao, Ctr Cell Based Therapy, FAPESP, CEPID, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Sch Med Ribeirao Preto FMRP, Dept Cellular & Mol Biol & Pathogen Bioagents, Ribeirao Preto - Brazil

^[4] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Biol, Ribeirao Preto - Brazil

^[5] Univ Sao Paulo, Sch Med Ribeirao Preto FMRP, Dept Internal Med, Ribeirao Preto - Brazil

• Document type: Journal article
• Source: FEBS OPEN BIO; v. 11, n. 7, p. 2019-2032, JUL 2021.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 13/01355-7 - In vitro and in vivo study of new compounds: with target-specific (hnRNP K) or action in the mitochondria for use as antitumor oral carcinoma or as cytoprotective in non-tumor cell
• Grantee: Renata Nishida Goto
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/00374-8 - Analysis of hnRNPK protein in cell lines NB4 and NB4-R2 of acute myeloid leukemia with emphasis in pathogenesis and cell differentiation by all-trans retinoic acid
• Grantee: Karina Stringhetta Padovani
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/10898-4 - Study of the molecular mechanisms by protein SET with impact on tumorigenesis and progression of oral cancer
• Grantee: Carlos Curti
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/19103-2 - SET and sphingolipids in head and neck squamous cell carcinoma: signaling, targets and antiumoral therapy
• Grantee: Andréia Machado Leopoldino
• Support Opportunities: Research Projects - Thematic Grants