SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation

Abstract

The mitochondrial serine hydroxymethyltransferase SHMT2, which catalyzes the rate-limiting step in serine catabolism, drives cancer cell proliferation, but how this role is regulated is undefined. Here, we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. Conversely, hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.Significance: These findings reveal a novel mechanism for controlling cancer cell proliferation by blocking serine catabolism, as a general strategy to impede tumor growth. Cancer Res; 78(2); 372-86.Ó2017 AACR.

Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma development and growth in vivo

“…In conclusion, unlike other types of cancers, Sirt5 loss of function showed no apparent effects in the melanoma models tested here. The dependency on Sirt5 ‐regulated function may be low in Braf V600E ‐induced melanoma cells, and thus, other molecular mechanisms may be able to compensate the lack of Sirt5 function.…”

“…Moreover, Sirt5 has been implicated as a regulator of cancer cell metabolism . However, there have been conflicting results in previous studies aimed at identifying a role for Sirt5 in cancer cells, as Sirt5 appears to act as both a tumor promoter and suppressor depending on the type of cancer . Furthermore, Sirt5 has been linked with chemotherapy resistance in colorectal cancer .…”

The catalytic activity of serine hydroxymethyltransferase is essential for de novo nuclear dTMP synthesis in lung cancer cells

“…It is important to notice that all the overexpressed mutants are expected to behave as dominant negative with respect to the endogenous wt enzyme, as previously shown for SHMT1-IT [17]. At this stage, we cannot exclude that a complex interplay between metabolic fluxes, active site conformational changes, nucleic acid binding or PTM (recently shown to regulate SHMT2 activity [16]) is actually operative and responsible for the fine tuning of SHMT isoforms levels. Based on these data, our current hypothesis on the nuclear function of SHMT1 is that in situ dTMP synthesis may proceeds through a substrate tunnelling mechanism.…”

“…2B [14]. A recent study shows that SHMT2 can be inactivated by succinylation of the catalytic lysine and that the modified enzyme is dimeric [16]. A recent study shows that SHMT2 can be inactivated by succinylation of the catalytic lysine and that the modified enzyme is dimeric [16].…”

“…A PLP-dependent change in the oligomeric state of SHMT, also observed for SHMT2 from Pichia pastoris [15], could in turn be related to different post-transcriptional modification (PTM) of the enzyme. A recent study shows that SHMT2 can be inactivated by succinylation of the catalytic lysine and that the modified enzyme is dimeric [16]. It is unclear whether the different conformational equilibria experienced by SHMT isoforms are in any way related to the protein ability to assemble the nuclear tertiary complex or may be involved in the cross-regulating mechanism between the two isoforms.…”