HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells.

Sharif, Tanveer; Martell, Emma; Dai, Cathleen; Ghassemi-Rad, Mohammad Saleh; Hanes, Mark Robert; Murphy, Patrick J; Margam, Nandini N; Parmar, Hirendrasinh B; Giacomantonio, Carman A; Duncan, Roy; Lee, Patrick W K; Gujar, Shashi

Sharif, Tanveer; Martell, Emma; Dai, Cathleen; Ghassemi-Rad, Mohammad Saleh; Hanes, Mark Robert; Murphy, Patrick J; Margam, Nandini N; Parmar, Hirendrasinh B; Giacomantonio, Carman A; Duncan, Roy; Lee, Patrick W K; Gujar, Shashi.

Afiliación

Sharif T; a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada.
Martell E; a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada.
Dai C; b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada.
Ghassemi-Rad MS; a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada.
Hanes MR; b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada.
Murphy PJ; a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada.
Margam NN; b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada.
Parmar HB; b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada.
Giacomantonio CA; b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada.
Duncan R; c Surgery , Dalhousie University , Halifax , Nova Scotia , Canada.
Lee PWK; b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada.
Gujar S; d Biochemistry and Molecular Biology , Dalhousie University , Halifax , Nova Scotia , Canada.

Autophagy ; 15(4): 686-706, 2019 04.

Article en En | MEDLINE | ID: mdl-30444165

RESUMEN

Cancer stem-like cells (CSCs), a small population of pluripotent cells residing within heterogeneous tumor mass, remain highly resistant to various chemotherapies as compared to the differentiated cancer cells. It is being postulated that CSCs possess unique molecular mechanisms, such as autophagic homeostasis, that allow CSCs to withstand the therapeutic assaults. Here we demonstrate that HDAC6 inhibition differentially modulates macroautophagy/autophagy in CSCs as compared to that of differentiated cancer cells. Using human and murine CSC models and differentiated cells, we show that the inhibition or knockdown (KD) of HDAC6 decreases CSC pluripotency by downregulating major pluripotency factors POU5F1, NANOG and SOX2. This decreased HDAC6 expression increases ACTB, TUBB3 and CSN2 expression and promotes differentiation in CSCs in an apoptosis-independent manner. Mechanistically, HDAC6 KD in CSCs decreases pluripotency by promoting autophagy, whereas the inhibition of pluripotency via retinoic acid treatment, POU5F1 or autophagy-related gene (ATG7 and ATG12) KD in CSCs decreases HDAC6 expression and promotes differentiation. Interestingly, HDAC6 KD-mediated CSC growth inhibition is further enhanced in the presence of autophagy inducers Tat-Beclin 1 peptide and rapamycin. In contrast to the results observed in CSCs, HDAC6 KD in differentiated breast cancer cells downregulates autophagy and increases apoptosis. Furthermore, the autophagy regulator p-MTOR, upstream negative regulators of p-MTOR (TSC1 and TSC2) and downstream effectors of p-MTOR (p-RPS6KB and p-EIF4EBP1) are differentially regulated in CSCs versus differentiated cancer cells following HDAC6 KD. Overall these data identify the differential regulation of autophagy as a molecular link behind the differing chemo-susceptibility of CSCs and differentiated cancer cells.

Asunto(s)

Autofagia/genética; Neoplasias de la Mama/metabolismo; Diferenciación Celular/genética; Histona Desacetilasa 6/antagonistas & inhibidores; Histona Desacetilasa 6/metabolismo; Células Madre Neoplásicas/metabolismo; Actinas/metabolismo; Animales; Apoptosis/genética; Proteína 12 Relacionada con la Autofagia/genética; Proteína 12 Relacionada con la Autofagia/metabolismo; Proteína 7 Relacionada con la Autofagia/genética; Proteína 7 Relacionada con la Autofagia/metabolismo; Neoplasias de la Mama/genética; Supervivencia Celular/genética; Femenino; Células HEK293; Histona Desacetilasa 6/genética; Humanos; Ratones; Proteína Homeótica Nanog/genética; Proteína Homeótica Nanog/metabolismo; Factor 3 de Transcripción de Unión a Octámeros/genética; Factor 3 de Transcripción de Unión a Octámeros/metabolismo; Proteoma/metabolismo; Factores de Transcripción SOXB1/genética; Factores de Transcripción SOXB1/metabolismo; Serina-Treonina Quinasas TOR/metabolismo; Proteína 1 del Complejo de la Esclerosis Tuberosa/antagonistas & inhibidores; Proteína 1 del Complejo de la Esclerosis Tuberosa/genética; Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismo; Proteína 2 del Complejo de la Esclerosis Tuberosa/antagonistas & inhibidores; Proteína 2 del Complejo de la Esclerosis Tuberosa/genética; Proteína 2 del Complejo de la Esclerosis Tuberosa/metabolismo

Palabras clave

Autophagy; HDAC6; cancer stem-like cells; differentiation; p-MTOR; pluripotency

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Células Madre Neoplásicas / Neoplasias de la Mama / Diferenciación Celular / Histona Desacetilasa 6 Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Autophagy Año: 2019 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos

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