TY - JOUR
T1 - Post-Translational Modifications of Histone Variants in the Absence and Presence of a Methionine-Depleting Enzyme in Normal and Cancer Cells
AU - Montalbano, Serena
AU - Raboni, Samanta
AU - Sidoli, Simone
AU - Mozzarelli, Andrea
AU - Bettati, Stefano
AU - Buschini, Annamaria
N1 - Funding Information:
S.R., S.B. and A.M. are indebted to Tatyana Demidkina for previous collaborative work aimed at the exploitation of MGL for cancer therapy. S.S. is grateful to the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant), to AFAR (Sagol Network GerOmic Award), to the Einstein Nathan Shock Center for the Biology of Aging, to Relay Therapeutics, to Deerfield (Xseed award), to the NIH P30 grant CA013330 47. This work has been carried out in the frame of the activities of the “COMP-HUB” Initiative, funded by the “Departments of Excellence” Project of the Italian Ministry for Education, University and Research (MIUR). We are also grateful for the support of the shared instrument grant NIH 1 S10 OD030286-01.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/1
Y1 - 2023/1
N2 - Methionine is an essential amino acid involved in the formation of polyamines and a precursor metabolite for DNA and protein methylation. The dependence of cancer cells on methionine has triggered extensive investigations aimed at its targeting for cancer therapy, including the exploitation as a therapeutic tool of methionine γ-lyase (MGL), a bacterial enzyme that degrades methionine, capable of inhibiting cancer cells growth due to methionine starvation. We have exploited the high-resolution power of mass spectrometry to compare the effects of reduced availability of the methyl donor SAM, induced by MGL treatment, on the post-translational modifications of the histone tails in normal Hs27 and cancer HT-29 cells. In the absence of MGL, our analysis detected a three-fold higher relative abundance of trimethylated K25 of H1.4 in HT-29 than Hs27 cells, and a complex pattern of methylated, unmethylated and acetylated peptides in H2 and H3.3. In the presence of MGL, in HT-29, the peptide H2A1_4_11 is predominantly unmodified with mono-methylated K5 increasing upon treatment, whereas in Hs27 cells, H2A1_4_11 is monomethylated at K5 and K9 with these marks decreasing upon treatment. The time dependence of the effects of MGL-mediated methionine depletion on PTMs of histone variants in HT-29 cancer cells was also monitored. Overall, our present data on histone variants H1, H2A, H2B as well as H3.3 integrated with our previous studies on histones H3 and H4, shed light on the epigenetic modifications associated with methionine starvation and associated cancer cell death.
AB - Methionine is an essential amino acid involved in the formation of polyamines and a precursor metabolite for DNA and protein methylation. The dependence of cancer cells on methionine has triggered extensive investigations aimed at its targeting for cancer therapy, including the exploitation as a therapeutic tool of methionine γ-lyase (MGL), a bacterial enzyme that degrades methionine, capable of inhibiting cancer cells growth due to methionine starvation. We have exploited the high-resolution power of mass spectrometry to compare the effects of reduced availability of the methyl donor SAM, induced by MGL treatment, on the post-translational modifications of the histone tails in normal Hs27 and cancer HT-29 cells. In the absence of MGL, our analysis detected a three-fold higher relative abundance of trimethylated K25 of H1.4 in HT-29 than Hs27 cells, and a complex pattern of methylated, unmethylated and acetylated peptides in H2 and H3.3. In the presence of MGL, in HT-29, the peptide H2A1_4_11 is predominantly unmodified with mono-methylated K5 increasing upon treatment, whereas in Hs27 cells, H2A1_4_11 is monomethylated at K5 and K9 with these marks decreasing upon treatment. The time dependence of the effects of MGL-mediated methionine depletion on PTMs of histone variants in HT-29 cancer cells was also monitored. Overall, our present data on histone variants H1, H2A, H2B as well as H3.3 integrated with our previous studies on histones H3 and H4, shed light on the epigenetic modifications associated with methionine starvation and associated cancer cell death.
KW - histone variants
KW - Hs27 cell line
KW - HT-29 cell line
KW - mass spectrometry
KW - methionine depletion
KW - methionine gamma-lyase
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U2 - 10.3390/cancers15020527
DO - 10.3390/cancers15020527
M3 - Article
AN - SCOPUS:85146549584
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 2
M1 - 527
ER -