GFI1-Dependent Repression of SGPP1 Increases Multiple Myeloma Cell Survival.
GFI1-Dependent Repression of SGPP1 Increases Multiple Myeloma Cell Survival.
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DOI：
10.3390/cancers14030772
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发表时间：
2022-02-02
期刊：
影响因子：
5.2
通讯作者：
Roodman GD
中科院分区：
文献类型：
--
作者：
Petrusca DN;Mulcrone PL;Macar DA;Bishop RT;Berdyshev E;Suvannasankha A;Anderson JL;Sun Q;Auron PE;Galson DL;Roodman GD
新的治疗方法极大地提高了“标准风险”多发性骨髓瘤(MM)患者的无进展和总体存活率。然而，“高危”MM患者，特别是其MM细胞携带无功能P53的患者，由于高度耐药MM的早期复发和快速发展，生存时间非常短。在本报告中，我们发现了一种新的机制，即生长因子独立1(GFI1)通过调节鞘磷脂代谢来调节MM细胞的生长和生存，而与其P53状态无关。我们发现鞘氨醇-1-磷酸酶(SGPP1)基因是MM细胞中GFI1转录抑制的一个新的直接靶点，从而增加细胞内鞘氨醇-1-磷酸水平，从而稳定c-Myc。我们的结果支持GFI1作为一种有吸引力的治疗靶点，用于所有类型的MM，包括具有非功能性p53的“高危”患者群体，以及一种可能的治疗其他类型表达高水平c-Myc的癌症的方法。由于耐药克隆的出现，多发性骨髓瘤(MM)对大多数患者来说仍然是无法治愈的。在此，我们报道了一种P53非依赖的机制，它通过调节鞘磷脂代谢来增加鞘氨醇-1-磷酸(S1P)水平，而与P53状态无关，从而促进生长因子独立-1(GFI1)支持MM细胞的存活。我们发现，控制S1P生物合成、SphK1、去磷酸化和SGPP1的酶的表达与MM细胞中GFI1的水平存在差异相关。我们在多发性骨髓瘤细胞SGGP1基因5‘端预测的增强子区域检测到GFI1在SGGP1基因上的占有率，这与GFI1高表达细胞中SGGP1表达降低和S1P水平升高相关，而与其P53状态无关。MM细胞内高S1P：神经酰胺比率以PP2A依赖的方式保护c-Myc蛋白的稳定性。抑制SphK1对MM细胞存活率的降低依赖于对p53WT和p53mut MM细胞自噬的诱导。自噬阻断仅在p53mut MM中阻止GFI1对存活率的支持，表明GFI1独立地通过抑制p53WT和上调S1P来提高MM细胞的存活率。因此，GFI1可能是所有类型MM的关键治疗靶点，对当前治疗高度耐药的患者可能会显著受益。
New therapies have greatly improved the progression-free and overall survival for patients with “standard risk” multiple myeloma (MM). However, patients with “high risk” MM, in particular patients whose MM cells harbor non-functional p53, have very short survival times because of the early relapse and rapid development of highly therapy-resistant MM. In this report, we identify a novel mechanism responsible for Growth Factor Independence-1 (GFI1) regulation of the growth and survival of MM cells through its modulation of sphingolipid metabolism, regardless of their p53 status. We identify the Sphingosine-1-Phosphate Phosphatase (SGPP1) gene as a novel direct target of GFI1 transcriptional repression in MM cells, thus increasing intracellular sphingosine-1-phosphate levels, which stabilizes c-Myc. Our results support GFI1 as an attractive therapeutic target for all types of MM, including the “high risk” patient population with non-functional p53, as well as a possible therapeutic approach for other types of cancers expressing high levels of c-Myc. Multiple myeloma (MM) remains incurable for most patients due to the emergence of drug resistant clones. Here we report a p53-independent mechanism responsible for Growth Factor Independence-1 (GFI1) support of MM cell survival by its modulation of sphingolipid metabolism to increase the sphingosine-1-phosphate (S1P) level regardless of the p53 status. We found that expression of enzymes that control S1P biosynthesis, SphK1, dephosphorylation, and SGPP1 were differentially correlated with GFI1 levels in MM cells. We detected GFI1 occupancy on the SGGP1 gene in MM cells in a predicted enhancer region at the 5’ end of intron 1, which correlated with decreased SGGP1 expression and increased S1P levels in GFI1 overexpressing cells, regardless of their p53 status. The high S1P:Ceramide intracellular ratio in MM cells protected c-Myc protein stability in a PP2A-dependent manner. The decreased MM viability by SphK1 inhibition was dependent on the induction of autophagy in both p53WT and p53mut MM. An autophagic blockade prevented GFI1 support for viability only in p53mut MM, demonstrating that GFI1 increases MM cell survival via both p53WT inhibition and upregulation of S1P independently. Therefore, GFI1 may be a key therapeutic target for all types of MM that may significantly benefit patients that are highly resistant to current therapies.
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影响因子：
11.4
作者：
Chng, W-J;Huang, G. F.;Chung, T. H.;Ng, S. B.;Gonzalez-Paz, N.;Troska-Price, T.;Mulligan, G.;Chesi, M.;Bergsagel, P. L.;Fonseca, R.
通讯作者：
Fonseca, R.
DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
3.7
作者：
Boyd, Kevin D.;Ross, Fiona M.;Morgan, Gareth J.
通讯作者：
Morgan, Gareth J.
影响因子：
45.3
作者：
Anguiano, Ariel;Tuchman, Sascha A.;Potti, Anil
通讯作者：
Potti, Anil
影响因子：
45.3
作者：
Avet-Loiseau, Herve;Attal, Michel;Moreau, Philippe
通讯作者：
Moreau, Philippe