PMID- 30444165 OWN - NLM STAT- MEDLINE DCOM- 20200511 LR - 20231213 IS - 1554-8635 (Electronic) IS - 1554-8627 (Print) IS - 1554-8627 (Linking) VI - 15 IP - 4 DP - 2019 Apr TI - HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells. PG - 686-706 LID - 10.1080/15548627.2018.1548547 [doi] AB - 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. FAU - Sharif, Tanveer AU - Sharif T AUID- ORCID: 0000-0002-0981-5615 AD - a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Martell, Emma AU - Martell E AD - a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Dai, Cathleen AU - Dai C AD - b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Ghassemi-Rad, Mohammad Saleh AU - Ghassemi-Rad MS AD - a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Hanes, Mark Robert AU - Hanes MR AD - b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Murphy, Patrick J AU - Murphy PJ AD - a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Margam, Nandini N AU - Margam NN AD - b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Parmar, Hirendrasinh B AU - Parmar HB AD - b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Giacomantonio, Carman A AU - Giacomantonio CA AD - b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada. AD - c Surgery , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Duncan, Roy AU - Duncan R AD - b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada. AD - d Biochemistry and Molecular Biology , Dalhousie University , Halifax , Nova Scotia , Canada. AD - e Pediatrics , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Lee, Patrick W K AU - Lee PWK AD - a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada. AD - b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada. FAU - Gujar, Shashi AU - Gujar S AD - a Deaprtment of Pathology , Dalhousie University , Halifax , Nova Scotia , Canada. AD - b Microbiology and Immunology , Dalhousie University , Halifax , Nova Scotia , Canada. AD - f Biology , Dalhousie University , Halifax , Nova Scotia , Canada. AD - g Centre for Innovative and Collaborative Health Systems Research , IWK Health Centre , Halifax , Nova Scotia , Canada. LA - eng GR - CAPMC/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181204 PL - United States TA - Autophagy JT - Autophagy JID - 101265188 RN - 0 (ATG12 protein, human) RN - 0 (Actins) RN - 0 (Autophagy-Related Protein 12) RN - 0 (Nanog Homeobox Protein) RN - 0 (Octamer Transcription Factor-3) RN - 0 (Proteome) RN - 0 (SOXB1 Transcription Factors) RN - 0 (TSC1 protein, human) RN - 0 (TSC2 protein, human) RN - 0 (Tuberous Sclerosis Complex 1 Protein) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.5.1.98 (HDAC6 protein, human) RN - EC 3.5.1.98 (Hdac6 protein, mouse) RN - EC 3.5.1.98 (Histone Deacetylase 6) RN - EC 6.2.1.45 (ATG7 protein, human) RN - EC 6.2.1.45 (Autophagy-Related Protein 7) SB - IM MH - Actins/metabolism MH - Animals MH - Apoptosis/genetics MH - Autophagy/*genetics MH - Autophagy-Related Protein 12/genetics/metabolism MH - Autophagy-Related Protein 7/genetics/metabolism MH - Breast Neoplasms/genetics/*metabolism MH - Cell Differentiation/*genetics MH - Cell Survival/genetics MH - Female MH - HEK293 Cells MH - Histone Deacetylase 6/*antagonists & inhibitors/genetics/*metabolism MH - Humans MH - Mice MH - Nanog Homeobox Protein/genetics/metabolism MH - Neoplastic Stem Cells/*metabolism MH - Octamer Transcription Factor-3/genetics/metabolism MH - Proteome/metabolism MH - SOXB1 Transcription Factors/genetics/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - Tuberous Sclerosis Complex 1 Protein/antagonists & inhibitors/genetics/metabolism MH - Tuberous Sclerosis Complex 2 Protein/antagonists & inhibitors/genetics/metabolism PMC - PMC6526821 OTO - NOTNLM OT - Autophagy OT - HDAC6 OT - cancer stem-like cells OT - differentiation OT - p-MTOR OT - pluripotency EDAT- 2018/11/18 06:00 MHDA- 2020/05/12 06:00 PMCR- 2019/12/04 CRDT- 2018/11/17 06:00 PHST- 2018/11/18 06:00 [pubmed] PHST- 2020/05/12 06:00 [medline] PHST- 2018/11/17 06:00 [entrez] PHST- 2019/12/04 00:00 [pmc-release] AID - 1548547 [pii] AID - 10.1080/15548627.2018.1548547 [doi] PST - ppublish SO - Autophagy. 2019 Apr;15(4):686-706. doi: 10.1080/15548627.2018.1548547. Epub 2018 Dec 4.